Therapeutic agents comprising elastic peptides

ABSTRACT

The present invention provides therapeutic agents and compositions comprising elastic peptides and therapeutic proteins. Such peptides exhibit a flexible, extended conformation. In some embodiments, the therapeutic protein is a GLP-1 receptor agonist (e.g., GLP-1, exendin), insulin, or Factor VII/VIIa, including functional analogs. The present invention further provides encoding polynucleotides, as well as methods of making and using the therapeutic agents. The therapeutic agents have improvements in relation to their use as therapeutics, including, inter alia, one or more of half-life, clearance and/or persistance in the body, solubility, and bioavailability.

PRIORITY

This application is a continuation of U.S. application Ser. No. 12/852,365, filed Aug. 6, 2010, which is a continuation-in-part of U.S. application Ser. No. 12/493,912, filed Jun. 29, 2009, which claims priority to U.S. Provisional Application No. 61/076,221, filed Jun. 27, 2008, each of which is hereby incorporated by reference in its entirety. This application is also a continuation-in-part of U.S. application Ser. No. 12/158,190, which is a U.S. national stage of PCT/US06/048572, filed Dec. 20, 2006, which claims priority to U.S. Provisional Application No. 60/751,896, filed Dec. 20, 2005, each of which is hereby incorporated by reference in its entirety.

GOVERNMENT SUPPORT

This invention was made with Government support under grant number EB00188 and GM-061232 from National Institutes of Health. The US Government has certain rights to this invention.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: PHAS_(—)021_(—)02US_SeqList_ST25.txt, date recorded: Mar. 11, 2013, file size 52 kb).

BACKGROUND OF THE INVENTION

Therapeutic proteins or peptides in their native state or when recombinantly produced can be labile molecules exhibiting, inter alia, short periods of serum stability, serum half-life (i.e., circulatory half-life), or limited persistance in the body. Such molecules can also be extremely labile when formulated, such as when formulated in aqueous solutions.

In some instances, polyethylene glycol (PEG) conjugated to a proteinaceous molecule results in a longer-acting, sustained activity of the molecule. PEG attachment, however, can often substantially reduce or even destroy the protein's therapeutic activity. Therapeutic proteins and/or peptides have also been stabilized by fusion to certain proteins that are capable of extending serum half-life. For example, in some instances, therapeutic proteins fused to albumin, transferrin, and antibody fragments exhibit extended serum half-life when compared to the therapeutic protein in the unfused state. See U.S. Pat. No. 7,238,667 (particularly with respect to albumin conjugates), U.S. Pat. No. 7,176,278 (particularly with respect to transferrin conjugates), and U.S. Pat. No. 5,766,883, which are each hereby incorporated by reference in their entireties.

There remains a need in the art for more stable, longer acting, and/or effective proteinaceous molecules.

SUMMARY OF THE INVENTION

The present invention provides therapeutic agents comprising an elastic peptide component and a therapeutic proteinacious component. The elastic peptide component may form a spiral conformation, and/or may have an extended structure relative to an alpha helix. The elastic peptide component may be structurally related to, or derived from, sequences of the elastin protein (elastin-like-peptide or ELP). Such elastic peptide components provide certain therapeutic advantages to the therapeutic agent, such as comparatively better stability, solubility, bioavailability, half-life, persistance, and/or biological action of the therapeutic proteinaceous component. Such properties may be determined, for example, with respect to the therapeutic component's unfused or unconjugated counterpart. In some embodiments, the elastic peptide is an ELP that undergoes a reversible inverse phase transition, which may impart additional practical and/or therapeutic advantages. The invention further provides polynucleotides encoding the therapeutic agents of the invention, as well as methods of treatment or prophylaxis for certain biological conditions.

In a first aspect, the invention provides a therapeutic agent comprising an elastic peptide component and a therapeutic proteinacious component, as well as pharmaceutical compositions containing the same for delivery to a subject or patient in need. The therapeutic component may be selected from active portions of the therapeutic proteins described herein, including those listed in Table 1, or functional analogs thereof. In certain embodiments, the therapeutic component is a GLP-1 receptor agonist, such as GLP-1, exendin-4, or a functional analog thereof. Such therapeutic components are generally effective for, among other things, increasing insulin secretion from the pancreas in a glucose-dependent manner. In other embodiments, the therapeutic component is an insulin or functional analog thereof, which is generally effective for promoting glucose uptake from the blood and storage within cells. In still other embodiments, the therapeutic component is a Factor VII/VIIa or functional analog thereof, which is generally effective for promoting coagulation by activation of Factor X or Factor IX.

The elastic peptide and therapeutic components may be covalently coupled by various means, including chemical coupling (e.g., conjugation) and recombinant fusion technology. In addition, the number of elastic peptide or therapeutic components per molecule, and their respective positions within the molecule, may vary as needed. The therapeutic agent may further include one or more spacer or linker moieties, which in addition to providing the desired functional independence of the elastic peptide and therapeutic components, may optionally provide for additional functionalities, such as a protease-sensitive feature to allow for proteolytic release or activation of the therapeutic component. The therapeutic agent may further include one or more targeting components such as, for example, a peptide or protein to target the therapeutic agent to a particular cell type, e.g., a cancer cell, or to a particular organ.

In a second aspect, the invention provides polynucleotides, such polynucleotides comprising a nucleotide sequence encoding a therapeutic agent of the invention. For example, the nucleotide sequence encodes an elastic peptide fusion with a functional portion of at least one therapeutic protein described herein, including those listed in Table 1 (or functional analog thereof). In certain embodiments, the therapeutic component is a GLP-1 receptor agonist (including GLP-1 and exendin-4), insulin, Factor VII/VIIa, or functional analog thereof. Such polynucleotides may further comprise additional control element(s) operably linked to the nucleotide sequence, such as promoter elements and/or other transcription or expression-related signals. The polynucleotide may be inserted into various vectors, which may be useful for production of the therapeutic agent in host cells, including, for example, bacterial and eukaryotic host cells.

In a third aspect, the invention provides a method for treating or preventing a disease, disorder, or condition in a subject, such as in a mammalian patient, including a human patient. The method comprises administering an effective amount of the therapeutic agent of the invention (or pharmaceutical composition containing the same) to a subject or patient in need thereof. For example, the patient may be in need of an agent having a biological activity or preferred indication listed herein (e.g., in Table 1). In certain embodiments employing a GLP-1 receptor agonist/elastic peptide compound or employing an insulin/elastic peptide compound, the invention provides a method for treating one or more disorders including type 1 or type 2 diabetes, hyperglycemia, and impaired glucose tolerance. In certain other embodiments employing Factor VII/VIIa/elastic peptide compound, the invention provides a method for treating one or more disorders including hemophilia, post-surgical bleeding, anticoagulation-induced bleeding, thrombocytopenia, factor VII deficiency, factor XI deficiency, and intracranial hemorrhage.

Various other aspects, features and embodiments of the invention will be more fully apparent from the following disclosure and appended claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts plasmid pET24d-ELP1-90, encoding an elastin-like-peptide (ELP) component with a 10 unit VPGXG (SEQ ID NO: 3) repeat motif, where guest position X is V, G, and A in the ratio of 5:3:2. This motif is repeated eight times with a final C-terminal 10-unit repeat where X is V, G, A, and W in the ratio 4:3:2:1. This ELP component is represented generally as [(VPGXG)₁₀]₉.

FIG. 2A depicts plasmid pET24d-Ex-4 ELP1-90 encoding an ELP component with VPGXG (SEQ ID NO: 3) repeat motif (as in FIG. 1) cloned in frame with an N-terminal exendin-4 component. FIG. 2B depicts the nucleotide and amino acid sequence of the exendin-4/ELP fusion (SEQ ID NOS: 23 and 24). Primer sequences are indicated (SEQ ID NOS:35-40).

FIG. 3A depicts the nucleotide and amino acid sequence of an exendin-4 construct having an N-terminal Tev (Tobacco Etch Virus cysteine protease) cleavage site (SEQ ID NOS: 25 and 26). Primer sequences are indicated (SEQ ID NOS:38, 41, 42).

FIG. 3B also depicts the nucleotide and amino acid sequence of an exendin-4 construct having an N-terminal Tev cleavage site, but with an additional sequence N-terminal to the Tev cleavage site to provide a better target for the protease (SEQ ID NOS: 27 and 28). Primer sequences are indicated (SEQ ID NOS:38, 43, 44).

FIG. 4A depicts the nucleotide and amino acid sequence of an exendin-4/ELP fusion as in FIGS. 1-3, but with a DsbA leader sequence to direct secretion into the periplasmic space (SEQ ID NOS: 29 and 30). Primer sequences are indicated (SEQ ID NOS:38, 45, 46). FIG. 4B depicts plasmid pET24d-DsbA-Ex-4 ELP1-90 encoding the fusion of FIG. 4A.

FIG. 5A depicts pPB0868, which encodes GLP-1 (A8G,7-37) ELP1-90.

FIG. 5B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 53 and 54, respectively).

FIG. 6A depicts pPB1022, which encodes GLP-1 (A8G,7-37) ELP1-120.

FIG. 6B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 55 and 56, respectively).

FIG. 7A depicts pPB0788, which encodes Factor VII-ELP1-90. FIG. 7B depicts the nucleotide and amino acid sequence of the encoded fusion protein (SEQ ID NOS: 57 and 58, respectively).

FIG. 8A depicts the nucleotide and amino acid sequence of an insulin (B, C, and A chains) having the ELP component cloned in frame (SEQ ID NOS: 31 and 32). Primer sequences are indicated (SEQ ID NOS: 47 and 48). FIG. 8B depicts plasmid pET24d Insulin-ELP1-90 expressing the insulin/ELP fusion of FIG. 8A.

FIG. 9 is a Western blot for FVII-ELP1-90 from transient transfection of Freestyle HEK293, detected with mouse anti-human FVII monoclonal antibody. Lanes are:

(1) culture media; (2) FVII ELP1-90 after purification by phase transition; and FVII control.

FIG. 10 is an SDS-PAGE showing recombinant production of an Exendin-4/ELP4-60 fusion. Lanes are: (M) Protein markers; (1) Exendin-4 ELP4-60 from total lysate; (2) Exendin-4 ELP4-60 from insoluble lysate; (3) Exendin-4 ELP4-60 from soluble lysate; (4) Exendin-4 ELP4-60 from 1st transition (equal volume); (5) Exendin-4 ELP4-60 from 2nd transition (concentrated); (6) Exendin-4 ELP4-60 from 3rd transition (concentrated).

FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. As shown, FactorVIIa-ELP retains full activity.

FIG. 12 shows that Factor VIIa-ELP1-90 has a long PK when administered by i.v. in rats. FactorVIIa has a T_(1/2) of about 690 min. as compared to about 45-60 min. for Factor VIIa.

FIG. 13 shows the high in vitro activity of GLP1-ELP and Exendin-4-ELP, when compared to the activity of Exendin peptide.

FIG. 14 shows that GLP1-ELP has a T_(1/2) of about 12.9 hours when administered by i.v. to rats, and a T_(1/2) of about 8.6 hours when administered subcutaneously (SQ).

FIG. 15 shows that GLP-1 ELP has a long half-life in rabbits of about 20 hours when administered i.v., and about 24 hours when administered sub-cutaneously.

FIG. 16 shows sustained glycemic control in diabetic mice with GLP-1-ELP.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides therapeutic agents comprising an elastic peptide component and a therapeutic component. The therapeutic component may be selected from Table 1 (e.g., selected from a Therapeutic Protein, or functional portion or functional analog thereof, listed in Table 1), or described herein. In certain embodiments, the therapeutic component is a GLP-1 receptor agonist, such as GLP-1 or exendin-4, or may be insulin, Factor VII/VIIa, or functional analog thereof. The elastic peptide component exhibits a flexibility and freedom of movement that results from its secondary structure characteristics, and overall or substantial lack of a rigid tertiary structure. The elastic peptide components may contain structural units related to, or derived from, sequences of the elastin protein. The elastic peptide provides certain therapeutic advantages, such as comparatively better persistence, stability, solubility, bioavailability, half-life, and/or biological action of the therapeutic component. Such properties may be determined with respect to, for example, an unfused or unconjugated counterpart of the therapeutic component. The invention further provides polynucleotides encoding the therapeutic agents of the invention, as well as methods of treatment or prophylaxis for certain biological conditions, including the preferred indications listed in Table 1, and including diabetes (e.g., Type I and Type II), hyperglycemia, bleeding, hemophilia, and hemorrhage, among others.

For ease of reference in the ensuing discussion, set out below are definitions of some terms appearing in the discussion.

As used herein, the term “therapeutic agent” or “therapeutic component” refers to an agent or component capable of inducing a biological effect in vivo and/or in vitro. The biological effect may be useful for treating and/or preventing a condition, disorder, or disease in a subject or patient.

As used herein, the term “coupled” means that the specified components are either directly covalently bonded to one another (e.g., via chemical conjugation or recombinant fusion technology), or indirectly covalently joined to one another (e.g., via chemical conjugation or recombinant fusion technology) through an intervening moiety or moieties, such as a bridge, spacer, or linker.

As used herein, “half-life” (which generally refers to in vivo half-life or circulatory half-life) is the period of time that is required for a 50% diminution of bioactivity of the active agent to occur. Such term is to be contrasted with “persistence,” which is the overall temporal duration of the active agent in the body, and “rate of clearance” as being a dynamically changing variable that may or may not be correlative with the numerical values of half-life and persistence.

The term “functional analog” refers to a protein that is an active analog (e.g., either chemical or protein analog), derivative, fragment, truncation isoform or the like of a native protein. For example, the functional analog may be a functional analog of a therapeutic protein listed in Table 1, or may be a functional analog of a GLP-1 receptor agonist (e.g., GLP-1, exendin), insulin, or Factor VII/VIIa. A polypeptide is active when it retains some or all of the biological activity of the corresponding native polypeptide, as determined in vivo or in one or more indicative in vitro assays. Exemplary activity assays for certain therapeutic proteins, which are determinative of activity, are listed Table 1. Further, such biological activities and assays for GLP-1 receptor agonists, insulin, and Factor VII/VIIa, which are determinative of whether a given molecule is a “functional analog,” are described in detail elsewhere herein.

As used herein, the term “native,” as used in reference to an amino acid sequence, indicates that the amino acid sequence is found in a naturally-occurring protein.

As used herein, the term “spacer” refers to any moiety, peptide or other chemical entity, that may be interposed between the elastic peptide component and the therapeutic component. For example, the spacer may be a divalent group that is covalently bonded at one terminus to the elastic peptide component, and covalently bonded at the other terminus to the therapeutic component. The therapeutic agents may therefore be open to the inclusion of additional chemical structure that does not preclude the efficacy of the agent for its intended purpose. The spacer may, for example, be a protease-sensitive spacer moiety that is provided to control the pharmacokinetics of the agent, or the spacer may be a protease-resistant moiety.

The therapeutic component and the elastic peptide component may be coupled with one another in any suitable covalent manner, including chemical coupling and recombinant technology, such that the therapeutic agent is efficacious for its intended purpose, and such that the presence of the elastic peptide component enhances the therapeutic component in some functional, therapeutic or physiological aspect. For example, the elastic peptide-coupled therapeutic component may be enhanced in, e.g., its bioavailability, bio-unavailability, therapeutically effective dose, biological action, formulation compatibility, resistance to proteolysis or other degradative modality, solubility, half-life or other measure of persistence in the body subsequent to administration, rate of clearance from the body subsequent to administration, etc. Such enhancement may be determined, for example, in relation to a corresponding unconjugated or unfused counterpart therapeutic (e.g., determined relative to native GLP-1, exendin, insulin, or Factor VII/VIIa, or a therapeutic protein described herein).

In some embodiments, the therapeutic agent of the invention circulates or exists in the body in a soluble form, and escapes filtration by the kidney thereby persisting in the body in an active form. In some embodiments, the therapeutic agents of the invention have a molecular weight of less than the generally recognized cut-off for filtration through the kidney, such as less than about 60 kD, or in some embodiments less than about 55, 50, 45, 40, 30, or 20 kDa, and persist in the body by at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 100-fold or longer than an uncoupled (e.g., unfused or unconjugated) therapeutic counterpart.

The number of elastic peptide and/or therapeutic components per molecule, and their respective positions within the molecule, may vary among embodiments of the invention. For example, in embodiments where the agent is a recombinant fusion, at least one elastic peptide component may be placed at one or both of the N-terminus and the C-terminus. Where the elastic peptide component is at both the N-terminus and C-terminus of the fusion, the elastic peptide components will flank the therapeutic component. Alternatively, the therapeutic component may be positioned at either or both of the N-terminus and C-terminus. Where the therapeutic component is at both the N-terminus and C-terminus, the therapeutic component will flank the elastic peptide component. In a further embodiment, different therapeutic components are positioned at the N-terminus and C-terminus of the molecule. As discussed in detail herein, in certain embodiments, such therapeutic component(s) may be released by proteolysis of a spacer moiety separating the elastic peptide and therapeutic components. In certain embodiments, the therapeutic component may be inactive in the fused state, and becoming active upon proteolytic release from the elastic peptide component(s). Alternatively, the therapeutic component remains active in the fused state, making proteolytic processing of the therapeutic agent unnecessary for biological activity.

When prepared as recombinant fusions, the therapeutic agent can be prepared by known recombinant expression techniques. For example, to recombinantly produce the therapeutic agent, a nucleic acid sequence encoding the chimeric gene is operatively linked to a suitable promoter sequence such that the nucleic acid sequence encoding such fusion protein will be transcribed and/or translated into the desired fusion protein in the host cells. Preferred promoters are those useful for expression in E. coli, such as the T7 promoter. Any commonly used expression system may be used, including eukaryotic or prokaryotic systems. Specific examples include yeast (e.g., Saccharomyces spp., Pichia spp.), baculovirus, mammalian, and bacterial systems, such as E. coli, and Caulobacter.

The various aspects and embodiments of the invention are described in greater detail in the following sections.

Elastic Peptide Component

The therapeutic agent of the invention may comprise one or more elastic peptide components. The elastic peptide components may comprise or consist of structural peptide units or sequences that are related to, or derived from, the elastin protein (e.g., elastin-like-peptides, or ELPs). Elastic peptides are useful for improving the properties of therapeutic proteins, such as those described herein (e.g., listed in Table 1), including GLP-1 receptor agonists (e.g., GLP-1 or exendin-4), insulin, and Factor VII/VIIa in one or more of bioavailability, therapeutically effective dose, biological action, formulation compatibility, resistance to proteolysis, solubility, half-life or other measure of persistence in the body subsequent to administration, and/or rate of clearance from the body.

The elastic peptide component may be constructed from structural units of from three to about twenty amino acids, or in some embodiments, from four to ten amino acids, such as five or six amino acids. The length of the individual structural units, may vary or may be uniform. In certain embodiments, the elastic peptide component is constructed of a polytetra-, polypenta-, polyhexa-, polyhepta-, polyocta, and polynonapeptide motif of repeating structural units. Exemplary structural units include units defined by SEQ ID NOS: 1-12 (below), which may be employed as repeating structural units, including tandem-repeating units, or may be employed in some combination, to create a peptide component effective for improving the properties of the therapeutic component. Thus, the elastic peptide component may comprise or consist essentially of structural unit(s) selected from SEQ ID NOS: 1-12, as defined below.

The elastic peptide component, comprising such structural units, may be of varying sizes. For example, the elastic peptide component may comprise or consist essentially of from about 10 to about 500 structural units, or in certain embodiments about 15 to about 150 structural units, or in certain embodiments from about 20 to about 100 structural units, or from about 50 to about 90 structural units, including one or a combination of units defined by SEQ ID NOS: 1-12. Thus, the elastic peptide component may have a length of from about 50 to about 2000 amino acid residues, or from about 100 to about 600 amino acid residues, or from about 200 to about 500 amino acid residues, or from about 200 to about 400 amino acid residues.

Elastic polymers (e.g., bioelastic polymers) are known and described in, for example, U.S. Pat. No. 5,520,672 to Urry et al. In general, elastic peptides comprise elastomeric units of bioelastic pentapeptides, tetrapeptides, and/or nonapeptides (e.g., elastin-like peptides). Thus, in some embodiments the elastomeric unit is a pentapeptide, in other embodiments the elastomeric unit is a tetrapeptide, and in still other embodiments the elastomeric unit is a nonapeptide. Bioelastic polymers that may be used to carry out the present invention are set forth in U.S. Pat. No. 4,474,851, which is hereby incorporated by reference in its entirety.

As disclosed in U.S. Pat. No. 4,474,851, elastomeric peptides may have a sequence of regularly appearing β-turns, forming an overall spiral conformation (e.g., a β-spiral, which is a series of regularly repeating β-turns). The spiral structures are more open than the more common α-helix. As a result, the atoms in the peptide backbone have a high freedom of movement (e.g., as compared to the freedom of movement for an α-helix). This is particularly true of librational motions involving peptide moieties. A libration is a torsional oscillation involving simultaneous rotational motions of the two single bonds on each side of a librating moiety. The moiety involved in a libration may be a single peptide bond or several peptide residues. For adequate freedom of motion to exist, it is important, however, that the carbonyl oxygen and the amino hydrogen of the peptide bond not be involved in hydrogen bonding to other parts of the molecule or to other molecules. Otherwise a greater energy barrier to the libration exists and motion will be restricted. Since non-hydrogen-bonded segments having freedom of motion exist in the β-spiral between the points of hydrogen bonding for the β-turns, these segments may be said to be librationally suspended. Librationally suspended segments therefore are a structural feature that exists in certain elastic peptides because of the repeating β-turns with relative infrequent hydrogen bonding. Librationally suspended segments resulting from the β-spiral structure are thought to give rise to elasticity, as will be further discussed.

Another factor leading to the high librational freedom of such molecules is the absence of significant polar interactions between the amino acid residues, either intrachain or interchain, other than a hydrogen bond within the β-turn. The amino acid residues present are mostly hydrophobic or glycine and accordingly do not exert significant forces on one another through space. If a significant number of charged or polar groups were present, electrostatic interactions might limit librational freedom and restrict the number of available states in the relaxed (non-extended) form of the molecules. Polar and charged amino acid residues are not strictly prohibited, however, if their presence does not destroy the elasticity of the eslatic peptide component as a whole. For example, an occasional serine residue is present in naturally occurring tropoelastin without destroying elasticity. Accordingly, hydrophobic amino acid residues and glycines are preferred in forming elastomeric polypeptides of the present type although other amino acids may be present to a some extent.

Although not intending to be bound by theory, the elasticity of polypeptides of the β-turn structure may be caused by thermodynamic drive toward greater entropy. The relaxed state of the β-spiral has a large degree of librational freedom and thus the atoms of the peptide chain can exist in a large number of positions. When the molecules are stretched, the degree of freedom is reduced, particularly for librational motions, and when the tension is released, a thermodynamic driving force toward higher entropy results in reformation of the contracted β-spiral.

Other specific bioelastic polymers that can be used to carry out the present invention are described in U.S. Pat. Nos. 4,132,746, 4,187,852, 4,500,700, 4,589,882, and 4,870,055, each of which are hereby incorporated by reference. Still other examples of bioelastic polymers are set forth in U.S. Pat. No. 6,699,294, U.S. Pat. No. 6,753,311, and U.S. Pat. No. 6,063,061, which are also incorporated by reference in their entirety.

In some embodiments, the β-turn may have the following structure, in the formation of a β-spiral:

wherein R1-R5 represent side chains of amino acid residues 1-5, and m is 0 when the repeating unit is a tetrapeptide or 1 when the repeating unit is a pentapeptide. Nonapeptide repeating units generally consist of sequential tetra- and pentapeptides. The amino acid residues may be hydrophobic amino acid residues, such as those independently selected from alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, and methionine. In many cases, the first amino acid residue of the repeating unit is a residue of valine, leucine, isoleucine or phenylalanine; the second amino acid residue is a residue of proline; the third amino acid residue is a residue of glycine; and the fourth amino acid residue is glycine or a hydrophobic residue such as tryptophan, phenylalanine or tyrosine.

In some embodiments, the elastic peptide component, or in some cases the therapeutic agent, has a size of less than about 65 kDa, or less than about 60 kDa, or less than about 55 kDa, or less than about 50 kDa, or less than about 40 kDa, or less than about 30 or 25 kDa. Three major blood proteins, Human Serum Albumin (HSA), Transferrin (Tf) and IgG, or the Fc portion of IgGs in their glycosylated form, have been exploited to extend the half-lives of proteins and peptides for improved therapeutic use. These molecules are 585, 679 and 480 amino acids in length giving molecular weights of about 66, 77, and ˜75 kDa (including glycosylations), respectively. They are each globular and relatively compact. The half life of these molecules is determined by a number of factors, including charge distribution, rescue of molecules by the neonatal Fc receptor (FcRn) (HSA and Fc) or cycling of Tf through the Tf receptor (TfR), and their size which prevents filtering through the kidney glomerulus. HSA is slightly below the generally regarded cut-off for filtration through the kidney (˜70 kDa) but its charge distribution helps prevent this. It would be anticipated that, in order to achieve half-life extension of the same order as that achieved with HSA, Tf and Fc, a protein of at least this molecular weight range would be required or desirable, i.e. having over 550 amino acids and being over 65 kDa. However, an elastic peptide with a small number of amino acids relative to HSA, Tf and Fc (e.g., in the range of about 300 to 400) and around 30 to 40 kDa may have a half life that matches and/or exceeds that of HSA, Tf, and Fc.

Thus, in some embodiments, the elastic peptide component may have an extended, relatively unstructured (e.g., no definitive tertiary structure due to rotational and/or librational freedom of the peptide backbone) and non-globular form, and thus such molecules may have a large expanded structure in comparison to HSA, Tf and Fc, so as to escape kidney filtration. In such embodiments, the therapeutic agents of the invention have a molecular weight of less than the generally recognized cut-off for filtration through the kidney, such as less than about 60 kD, or in some embodiments less than about 55, 50, 45, 40, 30, or 25 kDa, and persist in the body by at least 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 100-fold longer than an uncoupled (e.g., unfused or unconjugated) therapeutic counterpart.

In certain embodiments, the elastic peptide component is an ELP that undergoes a reversible inverse phase transition. ELP components are structurally disordered and highly soluble in water below a transition temperature (Tt), but exhibit a sharp (2-3° C. range) disorder-to-order phase transition when the temperature is raised above the Tt, leading to desolvation and aggregation of the ELP components. For example, the ELP forms insoluble polymers, when reaching sufficient size, which can be readily removed and isolated from solution by centrifugation. Such phase transition is reversible, and isolated insoluble ELPs can be completely resolubilized in buffer solution when the temperature is returned below the Tt of the ELPs. Thus, the therapeutic agents of the invention can, in some embodiments, be separated from other contaminating proteins to high purity using inverse transition cycling procedures, e.g., utilizing the temperature-dependent solubility of the therapeutic agent, or salt addition to the medium. Successive inverse phase transition cycles can be used to obtain a high degree of purity. In addition to temperature and ionic strength, other environmental variables useful for modulating the inverse transition of the therapeutic agents include pH, the addition of inorganic and organic solutes and solvents, side-chain ionization or chemical modification, and pressure.

In certain embodiments, the ELP component does not undergo a reversible inverse phase transition, or does not undergo such a transition at a biologically relevant Tt, and thus the improvements in the biological and/or physiological properties of the molecule (as described elsewhere herein), may be entirely or substantially independent of any phase transition properties. Nevertheless, such phase transition properties may impart additional practical advantages, for example, in relation to the recovery and purification of such molecules.

In certain embodiments, the ELP component(s) may be formed of structural units, including but not limited to:

-   -   (a) the tetrapeptide Val-Pro-Gly-Gly, or VPGG (SEQ ID NO: 1);     -   (b) the tetrapeptide Ile-Pro-Gly-Gly, or IPGG (SEQ ID NO: 2);     -   (c) the pentapeptide Val-Pro-Gly-X-Gly (SEQ ID NO: 3), or VPGXG,         where X is any natural or non-natural amino acid residue, and         where X optionally varies among polymeric or oligomeric repeats;     -   (d) the pentapeptide Ala-Val-Gly-Val-Pro, or AVGVP (SEQ ID NO:         4);     -   (e) the pentapeptide Ile-Pro-Gly-X-Gly, or IPGXG (SEQ ID NO: 5),         where X is any natural or non-natural amino acid residue, and         where X optionally varies among polymeric or oligomeric repeats;     -   (e) the pentapeptide Ile-Pro-Gly-Val-Gly, or IPGVG (SEQ ID NO:         6);     -   (f) the pentapeptide Leu-Pro-Gly-X-Gly, or LPGXG (SEQ ID NO: 7),         where X is any natural or non-natural amino acid residue, and         where X optionally varies among polymeric or oligomeric repeats;     -   (g) the pentapeptide Leu-Pro-Gly-Val-Gly, or LPGVG (SEQ ID NO:         8);     -   (h) the hexapeptide Val-Ala-Pro-Gly-Val-Gly, or VAPGVG (SEQ ID         NO: 9);     -   (I) the octapeptide Gly-Val-Gly-Val-Pro-Gly-Val-Gly, or GVGVPGVG         (SEQ ID NO: 10);     -   (J) the nonapeptide Val-Pro-Gly-Phe-Gly-Val-Gly-Ala-Gly, or         VPGFGVGAG (SEQ ID NO: 11); and     -   (K) the nonapeptides Val-Pro-Gly-Val-Gly-Val-Pro-Gly-Gly, or         VPGVGVPGG (SEQ ID NO: 12).

Such structural units defined by SEQ ID NOS:1-12 may form structural repeat units, or may be used in combination to form an ELP component in accordance with the invention. In some embodiments, the ELP component is formed entirely (or almost entirely) of one or a combination of (e.g., 2, 3 or 4) structural units selected from SEQ ID NOS: 1-12. In other embodiments, at least 75%, or at least 80%, or at least 90% of the ELP component is formed from one or a combination of structural units selected from SEQ ID NOS: 1-12, and which may be present as repeating units.

In certain embodiments, the ELP component(s) contain repeat units, including tandem repeating units, of the pentapeptide Val-Pro-Gly-X-Gly (SEQ ID NO:3), where X is as defined above, and where the percentage of Val-Pro-Gly-X-Gly (SEQ ID NO:3) pentapeptide units taken with respect to the entire ELP component (which may comprise structural units other than VPGXG (SEQ ID NO:3)) is greater than about 75%, or greater than about 85%, or greater than about 95% of the ELP component. The ELP component may contain motifs having a 5 to 15-unit repeat (e.g. about 10-unit repeat) of the pentapeptide of SEQ ID NO: 3, with the guest residue X varying among at least 2 or at least 3 of the units. The guest residues may be independently selected, such as from the amino acids V, I, L, A, G, and W (and may be selected so as to retain a desired inverse phase transition property). The repeat motif itself may be repeated, for example, from about 5 to about 12 times, such as about 8 to 10 times, to create an exemplary ELP component. The ELP component as described in this paragraph may of course be constructed from any one of the structural units defined by SEQ ID NOS: 1-12, or a combination thereof.

In some embodiments, the ELP component may include a β-turn structure. Exemplary peptide sequences suitable for creating a β-turn structure are described in International Patent Application PCT/US96/05186, which is hereby incorporated by reference in its entirety. For example, the fourth residue (X) in the elastin pentapeptide sequence, VPGXG (SEQ ID NO:3), can be altered without eliminating the formation of a β-turn. Alternatively, the ELP component may lack a β-turn, or otherwise have a different conformation and/or folding character.

In certain embodiments, the ELP components include polymeric or oligomeric repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where the guest residue X is any amino acid. X may be a naturally occurring or non-naturally occurring amino acid. In some embodiments, X is selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine. In some embodiments, X is a natural amino acid other than proline or cysteine.

The guest residue X (e.g., with respect to SEQ ID NO: 3, or other ELP structural unit) may be a non-classical (non-genetically encoded) amino acid. Examples of non-classical amino acids include: D-isomers of the common amino acids, 2,4-diaminobutyric acid, α-amino isobutyric acid, A-aminobutyric acid, Abu, 2-amino butyric acid, γ-Abu, ε-Ahx, 6-amino hexanoic acid, Aib, 2-amino isobutyric acid, 3-amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, β-alanine, fluoro-amino acids, designer amino acids such as β-methyl amino acids, Cα-methyl amino acids, Nα-methyl amino acids, and amino acid analogs in general.

Selection of X is independent in each ELP structural unit (e.g., for each structural unit defined herein having a guest residue X). For example, X may be independently selected for each structural unit as an amino acid having a positively charged side chain, an amino acid having a negatively charged side chain, or an amino acid having a neutral side chain, including in some embodiments, a hydrophobic side chain.

In still other embodiments, the ELP component(s) may include polymeric or oligomeric repeats of the pentapeptides VPGXG (SEQ ID NO:3), IPGXG (SEQ ID NO:5) or LPGXG (SEQ ID NO:7), or a combination thereof, where X is as defined above.

In each embodiment, the structural units, or in some cases polymeric or oligomeric repeats, of the elastic peptide sequences may be separated by one or more amino acid residues that do not eliminate the overall effect of the molecule, that is, in imparting certain improvements to the therapeutic component as described. In certain embodiments, such one or more amino acids also do not eliminate or substantially affect the phase transition properties where ELP components are employed (relative to the deletion of such one or more amino acids).

For ELP sequences, in each repeat, X is independently selected. The structure of the resulting ELP components may be described using the notation ELPk [X_(i)Y_(j)-n], where k designates a particular ELP repeat unit, the bracketed capital letters are single letter amino acid codes and their corresponding subscripts designate the relative ratio of each guest residue X in the structural units (where applicable), and n describes the total length of the ELP in number of the structural repeats. For example, ELP1 [V₅A₂G₃-10] designates an ELP component containing 10 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is valine, alanine, and glycine at a relative ratio of 5:2:3; ELP1 [K₁V₂F₁-4] designates an ELP component containing 4 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:2:1; ELP1 [K₁V₇F₁-9] designates a polypeptide containing 9 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:7:1; ELP1 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is exclusively valine; ELP1 [V-20] designates a polypeptide containing 20 repeating units of the pentapeptide VPGXG (SEQ ID NO:3), where X is exclusively valine; ELP2 [5] designates a polypeptide containing 5 repeating units of the pentapeptide AVGVP (SEQ ID NO:4); ELP3 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide IPGXG (SEQ ID NO:5), where X is exclusively valine; ELP4 [V-5] designates a polypeptide containing 5 repeating units of the pentapeptide LPGXG (SEQ ID NO:7), where X is exclusively valine. Such ELP components as described in this paragraph may be used in connection with the present invention to increase the therapeutic properties of the therapeutic component.

Further, the Tt is a function of the hydrophobicity of the guest residue. Thus, by varying the identity of the guest residue(s) and their mole fraction(s), ELPs can be synthesized that exhibit an inverse transition over a 0-100° C. range. Thus, the Tt at a given ELP length may be decreased by incorporating a larger fraction of hydrophobic guest residues in the ELP sequence. Examples of suitable hydrophobic guest residues include valine, leucine, isoleucine, phenyalanine, tryptophan and methionine. Tyrosine, which is moderately hydrophobic, may also be used. Conversely, the Tt may be increased by incorporating residues, such as those selected from the group consisting of: glutamic acid, cysteine, lysine, aspartate, alanine, asparagine, serine, threonine, glycine, arginine, and glutamine; preferably selected from alanine, serine, threonine and glutamic acid.

The ELP component in some embodiments is selected or designed to provide a Tt ranging from about 10 to about 80° C., such as from about 35 to about 60° C., or from about 38 to about 45° C. In some embodiments, the Tt is greater than about 40° C. or greater than about 42° C., or greater than about 45° C., or greater than about 50° C. The transition temperature, in some embodiments, is above the body temperature of the subject or patient (e.g., >37° C.) thereby remaining soluble in vivo, or in other embodiments, the Tt is below the body temperature (e.g., <37° C.) to provide alternative advantages, such as in vivo formation of a drug depot for sustained release of the therapeutic agent.

The Tt of the ELP component can be modified by varying ELP chain length, as the Tt generally increases with decreasing MW. For polypeptides having a molecular weight >100,000, the hydrophobicity scale developed by Urry et al. (PCT/US96/05186, which is hereby incorporated by reference in its entirety) is preferred for predicting the approximate Tt of a specific ELP sequence. However, in some embodiments, ELP component length can be kept relatively small, while maintaining a target Tt, by incorporating a larger fraction of hydrophobic guest residues (e.g., amino acid residues having hydrophobic side chains) in the ELP sequence. For polypeptides having a molecular weight<100,000, the Tt may be predicted or determined by the following quadratic function: Tt=M₀+M₁X+M₂X² where X is the MW of the fusion protein, and M₀=116.21; M₁=−1.7499; M₂=0.010349.

While the Tt of the ELP component, and therefore of the ELP component coupled to a therapeutic component, is affected by the identity and hydrophobicity of the guest residue, X, additional properties of the molecule may also be affected. Such properties include, but are not limited to solubility, bioavailability, persistence, and half-life of the molecule.

As described in PCT/US2007/077767 (published as WO 2008/030968), which is hereby incorporated by reference in its entirety, the ELP-coupled therapeutic component can retain the therapeutic component's biological activity. Additionally, ELPs themselves can exhibit long half-lives. Therefore, ELP components in accordance with the present invention substantially increase (e.g. by greater than 10%, 20%, 30%, 50%, 100%, 200%, 500% or more, in specific embodiments) the half-life of the therapeutic component when conjugated thereto. Such half-life (or in some embodiments persistance or rate of clearance) is determined in comparison to the half-life of the free (unconjugated or unfused) form of the therapeutic component. Furthermore, ELPs may target high blood content organs, when administered in vivo, and thus, can partition in the body, to provide a predetermined desired corporeal distribution among various organs or regions of the body, or a desired selectivity or targeting of a therapeutic agent. In sum, the therapeutic agents contemplated by the invention are administered or generated in vivo as active compositions having extended half-lives (e.g., circulatory half-life), among other potential benefits described herein.

The invention thus provides various agents for therapeutic (in vivo) application, where the therapeutic component is biologically active. Such therapeutic components include, without limitation, growth hormone (GH) particularly human and bovine growth hormone, growth hormone-releasing hormones; interferon including α-. β-, or γ-interferons, etc, interleukin-I; interleukin-II; erythropoietin including α- and β-erythropoietin (EPO), granulocyte colony stimulating factor (GCSF), granulocyte macrophage colony stimulating factor (GM-CSF), anti-agiogenic proteins (e.g., angiostatin, endostatin) PACAP polypeptide (pituitary adenylate cyclase activating polypeptide), vasoactive intestinal peptide (VIP), thyrotrophin releasing hormone (TRH), corticotropin releasing hormone (CRH), vasopressin, arginine vasopressin (AVP), angiotensin, calcitonin, atrial naturetic factor, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, insulin, somatotropin, plasminogen tissue activator, coagulation factors including coagulation factors VIII and IX, glucosylceramidase, sargramostim, lenograstin, filgrastin, dornase-α, molgramostim, PEG-L-asparaginase, PEG-adenosine deaminase, hirudin, eptacog-α (human blood coagulation factor VIIa) nerve growth factors, transforming growth factor, epidermal growth factor, basic fibroblast growth factor, VEGF; heparin including low molecular weight heparin, calcitonin; antigens; monoclonal antibodies; vancomycin; desferrioxamine (DFO); parathyroid hormone, an immunogen or antigen, an antibody such as a monoclonal antibody.

Where the therapeutic component is an antibody or antibody sequence, the antibody may be of any isotype, including IgG, IgM, IgA, IgD, and IgE. Where the antibody is IgG, the subtype may be IgG1, IgG2, IgG3, or IgG4. The antibody sequence may be humanized or chimeric. The term “antibody” as used herein includes antibody fragments or segments that retain the capability of binding to a target antigen, for example, Fab, F(ab′)2, and Fv fragments, and the corresponding fragments obtained from antibodies other than IgG. Examples of therapeutic antibodies include but are not limited to herceptin, rituxan, campath, gemtuzumab, herceptin, panorex, rituximab, bexxar, edrecolomab, alemtuzumab, mylotrag, IMC-C225, smartin 195, and mitomomab.

The therapeutic component may also be a therapeutic component listed in Table 1 (e.g., full length or functional portions or functional analogs thereof), as well as GLP-1 receptor agonists such as GLP-1 or exendin-4, insulin, or Factor VII/VIIa, and functional analogs thereof. The structure and activity of such therapeutic components are described in detail below. In some forms of the therapeutic agent, the coupling of the therapeutic component to the elastic peptide is effected by direct covalent bonding or indirect (through appropriate spacer groups) bonding (as described elsewhere herein). Further, the therapeutic component(s) and the elastic peptide component(s) can be structurally arranged in any suitable manner involving such direct or indirect covalent bonding, relative to one another.

Glucagon-Like Peptide (GLP)-1 Receptor Agonists

In certain embodiments of the invention, the therapeutic agent comprises an ELP component fused or conjugated to a GLP-1 receptor agonist, such as GLP-1, exendin-4, or functional analogs thereof.

Human GLP-1 is a 37 amino acid residue peptide originating from preproglucagon which is synthesized in the L-cells in the distal ileum, in the pancreas, and in the brain. Processing of preproglucagon to give GLP-1 (7-36)amide, GLP-1 (7-37) and GLP-2 occurs mainly in the L-cells. A simple system is used to describe fragments and analogs of this peptide. For example, Gly⁸-GLP-1 (7-37) designates a fragment of GLP-1 formally derived from GLP-1 by deleting the amino acid residues Nos. 1 to 6 and substituting the naturally occurring amino acid residue in position 8 (Ala) by Gly. Similarly, Lys³⁴ (NE-tetradecanoyl)-GLP-1 (7-37) designates GLP-1 (7-37) wherein the ε-amino group of the Lys residue in position 34 has been tetradecanoylated. Where reference in this text is made to C-terminally extended GLP-1 analogues, the amino acid residue in position 38 is Arg unless otherwise indicated, the optional amino acid residue in position 39 is also Arg unless otherwise indicated and the optional amino acid residue in position 40 is Asp unless otherwise indicated. Also, if a C-terminally extended analogue extends to position 41, 42, 43, 44 or 45, the amino acid sequence of this extension is as in the corresponding sequence in human preproglucagon unless otherwise indicated.

The parent peptide of GLP-1, proglucagon (PG), has several cleavage sites that produce various peptide products dependent on the tissue of origin including glucagon (PG[32-62]) and GLP-1 [7-36]NH₂ (PG[72-107]) in the pancreas, and GLP-1 [7-37] (PG[78-108]) and GLP-1 [7-36]NH₂ (PG [78-107]) in the L cells of the intestine where GLP-1 [7-36]NH₂ (78-107 PG) is the major product. The GLP-1 component in accordance with the invention may be any biologically active product or deivative of proglocagon, or functional analog thereof, including: GLP-1 (1-35), GLP-1 (1-36), GLP-1 (1-36)amide, GLP-1 (1-37), GLP-1 (1-38), GLP-1 (1-39), GLP-1 (1-40), GLP-1 (1-41), GLP-1 (7-35), GLP-1 (7-36), GLP-1 (7-36)amide, GLP-1 (7-37), GLP-1 (7-38), GLP-1 (7-39), GLP-1 (7-40) and GLP-1 (7-41), or a analog of the foregoing. Generally, the GLP-1 component in some embodiments may be expressed as GLP-1 (A-B), where A is an integer from 1 to 7 and B is an integer from 38 to 45, optionally with one or more amino acid substitutions as defined below.

As an overview, after processing in the intestinal L-cells, GLP-1 is released into the circulation, most notably in response to a meal. The plasma concentration of GLP-1 rises from a fasting level of approximately 15 pmol/L to a peak postprandial level of 40 pmol/L. For a given rise in plasma glucose concentration, the increase in plasma insulin is approximately threefold greater when glucose is administered orally compared with intravenously (Kreymann et al., 1987, Lancet 2(8571): 1300-4). This alimentary enhancement of insulin release, known as the incretin effect, is primarily humoral and GLP-1 is now thought to be the most potent physiological incretin in humans. GLP-1 mediates insulin production via binding to the GLP-1 receptor, known to be expressed in pancreatic β cells. In addition to the insulinotropic effect, GLP-1 suppresses glucagon secretion, delays gastric emptying (Wettergen et al., 1993, Dig Dis Sci 38: 665-73) and may enhance peripheral glucose disposal (D'Alessio et al., 1994, J. Clin Invest 93: 2293-6).

A combination of actions gives GLP-1 unique therapeutic advantages over other agents currently used to treat non-insulin-dependent diabetes mellitus (NIDDM). First, a single subcutaneous dose of GLP-1 can completely normalize post prandial glucose levels in patients with NIDDM (Gutniak et al., 1994, Diabetes Care 17: 1039-44). This effect may be mediated both by increased insulin release and by a reduction in glucagon secretion. Second, intravenous infusion of GLP-1 can delay postprandial gastric emptying in patients with NIDDM (Williams et al., 1996, J. Clin Endo Metab 81: 327-32). Third, unlike sulphonylureas, the insulinotropic action of GLP-1 is dependent on plasma glucose concentration (Holz et al., 1993, Nature 361:362-5). Thus, the loss of GLP-1-mediated insulin release at low plasma glucose concentration protects against severe hypoglycemia.

When given to healthy subjects, GLP-1 potently influences glycemic levels as well as insulin and glucagon concentrations (Orskov, 1992, Diabetologia 35:701-11), effects which are glucose dependent (Weir et al., 1989, Diabetes 38: 338-342). Moreover, it is also effective in patients with diabetes (Gutniak, M., 1992, N. Engl J Med 226: 1316-22), normalizing blood glucose levels in type 2 diabetic subjects and improving glycemic control in type 1 patients (Nauck et al., 1993, Diabetologia 36: 741-4, Creutzfeldt et al., 1996, Diabetes Care 19:580-6).

GLP-1 is, however, metabolically unstable, having a plasma half-life (t_(1,2)) of only 1-2 minutes in vivo. Moreover, exogenously administered GLP-1 is also rapidly degraded (Deacon et al., 1995, Diabetes 44: 1126-31). This metabolic instability has limited the therapeutic potential of native GLP-1.

GLP-1 [7-36]NH₂ has the following amino acid sequence: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 13), which may be employed as the GLP-1 component in accordance with the invention. Alternatively, the GLP-1 component may contain glycine (G) at the second position, giving, for example, the sequence HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR (SEQ ID NO: 17). The GLP-1 component may be a biologically active fragment of GLP-1, for example, as disclosed in US 2007/0041951, which is hereby incorporated by reference in its entirety. Other fragments and modified sequences of GLP-1 are known in the art (U.S. Pat. No. 5,614,492; U.S. Pat. No. 5,545,618; European Patent Application, Publication No. EP 0658568 A1; WO 93/25579, which are hereby incorporated by reference in their entireties). Such fragments and modified sequences may be used in connection with the present invention, as well as those described below.

Certain structural and functional analogs of GLP-1 have been isolated from the venom of the Gila monster lizards (Heloderma suspectum and Heloderma horridum) and have shown clinical utility. Such molecules find use in accordance with the present invention. In particular, exendin-4 is a 39 amino acid residue peptide isolated from the venom of Heloderma suspectum and shares approximately 52% homology with human GLP-1. Exendin-4 is a potent GLP-1 receptor agonist that stimulates insulin release, thereby lowering blood glucose levels. Exendin-4 has the following amino acid sequence: HGEGTFTSDLSKQMEEEAVRLFEWLKNGGPSSGAPPPS (SEQ ID NO: 14). A synthetic version of exendin-4 known as exenatide (marketed as Byetta®) has been approved for the treatment of Type-2 Diabetes. Although exenatide is structurally analogous to native GLP-1, it has a longer half-life after injection.

While exenatide has the ability to lower blood glucose levels on its own, it can also be combined with other medications such as metformin, a thiozolidinedione, a sulfonylureas, and/or insulin to improve glucose control. Exenatide is administered by injection subcutaneously twice per day using a pre-filled pen device. Typical human responses to exenatide include improvements in the initial rapid release of endogenous insulin, an increase in β-cell growth and replication, suppression of pancreatic glucagon release, delayed gastric emptying, and reduced appetite—all of which function to lower blood glucose. Unlike sulfonylureas and meglitinides, exenatide increases insulin synthesis and secretion in the presence of glucose only, thus lessening the risk of hypoglycemia. Despite the therapeutic utility of exenatide, it has certain undesirable traits, including the requirement of twice daily injections, gastrointestional side effects, and similar to native GLP-1, a relatively short half-life (i.e. approximately 2 hr).

Various functional analogs of GLP-1 and exendin-4 are known, and which find use in accordance with the invention. These include liraglutide (Novo Nordisk, WO98/008871), R1583/taspoglutide (Roche, WO00/034331), CJC-1131 (ConjuChem, WO00/069911), ZP-10/AVE0010 (Zealand Pharma, Sanofi-Aventis, WO01/004156), and LY548806 (Eli Lilly, WO03/018516).

Liraglutide, also known as NN2211, is a GLP-1 receptor agonist analog that has been designed for once-daily injection (Harder et al., 2004, Diabetes Care 27: 1915-21). Liraglutide has been tested in patients with type-2 diabetes in a number of studies and has been shown to be effective over a variety of durations. In one study, treatment with liraglutide improved glycemic control, improved β-cell function, and reduced endogenous glucose release in patients with type-2 diabetes after one week of treatment (Degn et al., 2004, Diabetes 53: 1187-94). In a similar study, eight weeks of 0.6-mg liraglutide therapy significantly improved glycemic control without increasing weight in subjects with type 2 diabetes compared with those on placebo (Harder et al., 2004, Diabetes Care 27: 1915-21).

Thus, in certain embodiments, the GLP-1 receptor agonist in accordance with the invention is as described in WO98/008871, which is hereby incorporated by reference in its entirety. The GLP-1 receptor agonist may have at least one lipophilic substituent, in addition to one, two, or more amino acid substitutions with respect to native GLP-1. For example, the lipophilic substituent may be an acyl group selected from CH₃(CH₂)_(n)CO—, wherein n is an integer from 4 to 38, such as an integer from 4 to 24. The lipophilic substituent may be an acyl group of a straight-chain or branched alkyl or fatty acid (for example, as described in WO98/008871, which description is hereby incorporated by reference).

In certain embodiments, the GLP-1 component is Arg²⁶-GLP-1 (7-37), Arg³⁴-GLP-1 (7-37), Lys³⁶-GLP-1 (7-37), Arg^(26,34)Lys³⁶-GLP-I (7-37), Arg^(26,34)Lys³⁸-GLP-I (7-38), Arg^(28,34)Lys³⁹-GLP-1 (7-39), Arg^(26,34)Lys⁴⁰-GLP-1 (7-40), Arg²⁶Lys³⁶-GLP-1 (7-37), Arg³⁴Lys³⁶-GLP-1 (7-37), Arg²⁶Lys³⁹-GLP-1 (7-39), Arg³⁴Lys⁴⁰-GLP-1 (7-40), Arg^(26,34)Lys^(36,39)-GLP-I (7-39), Arg^(26,34)Lys^(36,40)-GLP-1 (7-40), Gly⁸Arg²⁶-GLP-1 (7-37); Gly⁸Arg³⁴-GLP-1 (7-37); Gly⁸Lys³⁸-GLP-1 (7-37); Gly⁸Arg^(26,34)Lys³⁶-GLP-1 (7-37), Gly⁸Arg^(26,34)Lys³⁹-GLP-1 (7-39), Gly⁸Arg^(26,34)Lys⁴⁰-GLP-1 (7-40), Gly⁸Arg²⁶Lys³⁶-GLP-1 (7-37), Gly⁸Arg³⁴Lys³⁶-GLP-1 (7-37), Gly⁸Arg²⁶Lys³⁹-GLP-1 (7-39); Gly⁸Arg³⁴Lys⁴⁰-GLP-1 (7-40), Gly⁸Arg^(28,34)Lys^(36,39)-GLP-1 (7-39) and Gly⁸Arg^(26,34)Lys^(35,40)-GLP-1 (7-40), each optionally having a lipophilic substituent. For example, the GLP-1 receptor agonist may have the sequence/structure Arg³⁴Lys²⁶-(N-ε-(γ-Glu(N-α-hexadecanoyl)))-GLP-I (7-37).

Taspoglutide, also known as R1583 or BIM 51077, is a GLP-1 receptor agonist that has been shown to improve glycemic control and lower body weight in subjects with type 2 diabetes mellitus treated with metformin (Abstract No. A-1604, Jun. 7, 2008, 68th American Diabetes Association Meeting, San Francisco, Calif.).

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO00/034331, which is hereby incorporated by reference in its entirety. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence [Aib^(8,35)]hGLP-1 (7-36) NH₂ (e.g. taspoglutide), wherein Aib is alpha-aminoisobutyric acid.

CJC-1131 is a GLP-1 analog that consists of a DPP-IV-resistant form of GLP-1 joined to a reactive chemical linker group that allows GLP-1 to form a covalent and irreversible bond with serum albumin following subcutaneous injection (Kim et al., 2003, Diabetes 52: 751-9). In a 12-week, randomized, double-blind, placebo-controlled multicenter study, CJC-1131 and metformin treatment was effective in reducing fasting blood glucose levels in type 2 diabetes patients (Ratner et al., Abstract No. 10-OR, Jun. 10-14, 2005, 65th American Diabetes Association Meeting, San Francisco, Calif.).

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO00/069911, which is hereby incorporated by reference in its entirety. In some embodiments, the GLP-1 receptor agonist is modified with a reactive group which reacts with amino groups, hydroxyl groups or thiol groups on blood components to form a stable covalent bond. In certain embodiments, the GLP-1 receptor agonist is modified with a reactive group selected from the group consisting of succinimidyl and maleimido groups. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence/structure: D-Ala⁸Lys³⁷-(2-(2-(2-maleimidopropionamido(ethoxy)ethoxy)acetamide))-GLP-1 (7-37) (e.g. CJC-1131).

AVE0010, also known as ZP-10, is a GLP-1 receptor agonist that may be employed in connection with the invention. In a recent double-blind study, patients treated with once daily dosing of AVE0010 demonstrated significant reductions in HbA1c levels (Ratner et al., Abstract No. 433-P, 68th American Diabetes Association Meeting, San Francisco, Calif.). At the conclusion of the study, the percentages of patients with HbA1c<7% ranged from 47-69% for once daily dosing compared to 32% for placebo. In addition, AVE0010 treated patients showed dose-dependent reductions in weight and post-prandial plasma glucose.

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO01/004156, which is hereby incorporated by reference in its entirety. For example, the GLP-1 receptor agonist may have the sequence: HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2 (SEQ ID NO: 18) (e.g. AVE0010).

LY548806 is a GLP-1 derivative designed to be resistant to proteolysis by dipeptidase-peptidyl IV (DPP-IV) (Jackson et al., Abstract No. 562, Jun. 10-14, 2005, 65th American Diabetes Association Meeting, San Francisco, Calif.). In an animal model of hyperglycemia, LY548806 has been shown to produce a significant lowering of blood glucose levels during the hyperglycemic phase (Saha et al., 2006, J. Pharm. Exp. Ther. 316: 1159-64). Moreover, LY548806 was shown to produce a significant increase in insulin levels consistent with its known mechanism of action, namely stimulation of insulin release in the presence of hyperglycemia.

Thus, in certain embodiments, the GLP-1 receptor agonist is as described in WO03/018516, which is hereby incorporated by reference in its entirety. In some embodiments, the therapeutic agents of the present invention comprise GLP-1 analogs wherein the backbone for such analogs or fragments contains an amino acid other than alanine at position 8 (position 8 analogs). The backbone may also include L-histidine, D-histidine, or modified forms of histidine such as desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine, or α-methyl-histidine at position 7. In some embodiments, these position 8 analogs may contain one or more additional changes at positions 12, 16, 18, 19, 20, 22, 25, 27, 30, 33, and 37 compared to the corresponding amino acid of native GLP-1. In other embodiments, these position 8 analogs may contain one or more additional changes at positions 16, 18, 22, 25 and 33 compared to the corresponding amino acid of native GLP-1. In certain exemplary embodiments, the GLP-1 receptor agonist has the sequence: HVEGTFTSDVSSYLEEQAAKEFIAWLIKGRG-OH (SEQ ID NO: 19) (e.g. LY548806).

Thus, the present invention provides therapeutic agents comprising an elastic peptide (e.g., an ELP) and a GLP-1 receptor agonist. For example, in certain embodiments, the GLP-1 receptor agonist is GLP-1 (SEQ ID NO:13, 17, or 59) or a functional analog thereof. In other embodiments, the GLP-1 receptor agonist is exendin-4 (SEQ ID NO:14) or a functional analog thereof. Such functional analogs of GLP-1 or exendin-4 include functional fragments truncated at the C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, or up to about 5 amino acids (with respect to SEQ ID NOS: 13, 14, 17, or 59). Such functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NOS 13, 14, and 59), and in each case retaining the activity of the peptide. For example, the functional analog of GLP-1 or exendin-4 may have from 1 to about 3, 4, or 5 insertions, deletions and/or substitutions (collectively) with respect to SEQ ID NOS: 13, 59 and 14, and in each case retaining the activity of the peptide. Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the GLP-1 receptor agonist component has at least about 50%, 75%, 80%, 85%, 90%, or 95% identity with the native sequence (SEQ ID NOS: 13, 59, and 14). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide sequences, FEMS Microbiol Lett. 174:247-250 (1999). Such functional analogs may further comprise additional chemical modifications, such as those described in this section and/or others known in the art.

In certain embodiments, the GLP1-ELP fusion has a sequence exemplified herein as SEQ ID NOS: 54 and 56. When processed, the mature form of such fusion protein will begin with the His⁷ GLP.

In another aspect, the present invention provides methods for the treatment or prevention of type 2 diabetes, impaired glucose tolerance, type 1 diabetes, hyperglycemia, obesity, binge eating, bulimia, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, non-fatty liver disease, myocardial infarction, coronary heart disease and other cardiovascular disorders. The method comprises administering the therapeutic agent comprising the elastin-like peptide (ELP) and the GLP-1 receptor agonist (as described above) to a patient in need of such treatment. In these or other embodiments, the present invention provides methods for decreasing food intake, decreasing β-cell apoptosis, increasing β-cell function and β-cell mass, and/or for restoring glucose sensitivity to β-cells. Generally, the patient may be a human or non-human animal patient (e.g., dog, cat, cow, or horse). Preferably, the patient is human.

The treatment with a ELP/GLP-1 receptor agonist compound according to the present invention may also be combined with one or more pharmacologically active substances, e.g. selected from antidiabetic agents, antiobesity agents, appetite regulating agents, antihypertensive agents, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity. In the present context, the expression “antidiabetic agent” includes compounds for the treatment and/or prophylaxis of insulin resistance and diseases wherein insulin resistance is the pathophysiological mechanism.

The ability of a GLP-1 or exendin-4 analog, or an GLP-1 receptor agonist/elastic peptide compound, to bind the GLP-1 receptor may be determined by standard methods, for example, by receptor-binding activity screening procedures which involve providing appropriate cells that express the GLP-1 receptor on their surface, for example, insulinoma cell lines such as RINmSF cells or INS-1 cells. In addition to measuring specific binding of tracer to membrane using radioimmunoassay methods, cAMP activity or glucose dependent insulin production can also be measured. In one method, a polynucleotide encoding the GLP-1 receptor is employed to transfect cells to thereby express the GLP-1 receptor protein. Thus, these methods may be employed for testing or confirming whether a suspected GLP-1 receptor agonist is active. An exemplary assay is described in greater detail herein.

In addition, known methods can be used to measure or predict the level of biologically activity of a GLP-1 receptor agonist or GLP-1 receptor agonist/elastic peptide in vivo (See e.g. Siegel, et al., 1999, Regul Pept 79(2-3): 93-102). In particular, GLP-1 receptor agonists or GLP-1 receptor agonist/elastic peptide compounds can be assessed for their ability to induce the production of insulin in vivo using a variety of known assays for measuring GLP-1 activity. For example, a GLP-1 receptor agonist/elastic peptide compound can be introduced into a cell, such as an immortalized β-cell, and the resulting cell can be contacted with glucose. If the cell produces insulin in response to the glucose, then the modified GLP-1 is generally considered biologically active in vivo (Fehmann et al., 1992, Endocrinology 130: 159-166). An exemplary assay is described in greater detail herein.

The ability of an GLP-1 receptor agonist/elastic peptide compound to enhance β-cell proliferation, inhibit β-cell apoptosis, and regulate islet growth may also be measured using known assays. Pancreatic β-cell proliferation may be assessed by ³H-tymidine or BrdU incorporation assays (See e.g. Buteau et al., 2003, Diabetes 52: 124-32), wherein pancreatic β-cells such as INS (832/13) cells are contacted with a GLP-1 receptor agonist/elastic peptide compound and analyzed for increases in ³H-thymidine or BrdU incorporation. The antiapoptotic activity of a GLP-1 receptor agonist/elastic peptide compound can be measured in cultured insulin-secreting cells and/or in animal models where diabetes occurs as a consequence of an excessive rate of beta-cell apoptosis (See e.g. Bulotta et al., 2004, Cell Biochem Biophys 40(3 suppl): 65-78).

In addition to GLP-1, other peptides of this family, such as those derived from processing of the pro-glucagon gene, such as GLP-2, GIP, and oxyntomodulin, could be conjugated or fused to the elastic peptide component (as described herein) to enhance the therapeutic potential.

Insulin

In other embodiments, the present invention provides a therapeutic agent comprising an elastin peptide component coupled to insulin (e.g., via fusion or conjugation). Insulin injections, e.g. of human insulin, can be used to treat diabetes. The insulin-making cells of the body are called β-cells, and they are found in the pancreas gland. These cells clump together to form the “islets of Langerhans”, named for the German medical student who described them.

The synthesis of insulin begins at the translation of the insulin gene, which resides on chromosome 11. During translation, two introns are spliced out of the mRNA product, which encodes a protein of 110 amino acids in length. This primary translation product is called preproinsulin and is inactive. It contains a signal peptide of 24 amino acids in length, which is required for the protein to cross the cell membrane.

Once the preproinsulin reaches the endoplasmic reticulum, a protease cleaves off the signal peptide to create proinsulin. Proinsulin consists of three domains: an amino-terminal B chain, a carboxyl-terminal A chain, and a connecting peptide in the middle known as the C-peptide. Insulin is composed of two chains of amino acids named chain A (21 amino acids-GIVEQCCASVCSLYQLENYCN) (SEQ ID NO: 15) and chain B (30 amino acids FVNQHLCGSHLVEALYLVCGERGFFYTPKA) (SEQ ID NO: 16) that are linked together by two disulfide bridges. There is a 3rd disulfide bridge within the A chain that links the 6th and 11th residues of the A chain together. In most species, the length and amino acid compositions of chains A and B are similar, and the positions of the three disulfide bonds are highly conserved. For this reason, pig insulin can replace deficient human insulin levels in diabetes patients. Today, porcine insulin has largely been replaced by the mass production of human proinsulin by bacteria (recombinant insulin).

Insulin molecules have a tendency to form dimers in solution, and in the presence of zinc ions, insulin dimers associate into hexamers. Whereas monomers of insulin readily diffuse through the blood and have a rapid effect, hexamers diffuse slowly and have a delayed onset of action. In the design of recombinant insulin, the structure of insulin can be modified in a way that reduces the tendency of the insulin molecule to form dimers and hexamers but that does not interrupt binding to the insulin receptor. In this way, a range of preparations are made, varying from short acting to long acting.

Within the endoplasmic reticulum, proinsulin is exposed to several specific peptidases that remove the C-peptide and generate the mature and active form of insulin. In the Golgi apparatus, insulin and free C-peptide are packaged into secretory granules, which accumulate in the cytoplasm of the β-cells. Exocytosis of the granules is triggered by the entry of glucose into the beta cells. The secretion of insulin has a broad impact on metabolism.

There are two phases of insulin release in response to a rise in glucose. The first is an immediate release of insulin. This is attributable to the release of preformed insulin, which is stored in secretory granules. After a short delay, there is a second, more prolonged release of newly synthesized insulin.

Once released, insulin is active for a only a brief time before it is degraded by enzymes. Insulinase found in the liver and kidneys breaks down insulin circulating in the plasma, and as a result, insulin has a half-life of only about 6 minutes. This short duration of action results in rapid changes in the circulating levels of insulin.

Insulin analogs have been developed with improved therapeutic properties (Owens et al., 2001, Lancet 358: 739-46; Vajo et al., 2001, Endocr Rev 22: 706-17), and such analogs may be employed in connection with the present invention. Various strategies, including elongation of the COOH-terminal end of the insulin B-chain and engineering of fatty acid-acylated insulins with substantial affinity for albumin are used to generate longer-acting insulin analogs. However, in vivo treatments with available longer-acting insulin compounds still result in a high frequency of hypo- and hyperglycemic excursions and modest reduction in HbA_(1c). Accordingly, development of a truly long-acting and stable human insulin analog still remains an important task.

Functional analogs of insulin that may be employed in accordance with the invention include rapid acting analogs such as lispro, aspart and glulisine, which are absorbed rapidly (<30 minutes) after subcutaneous injection, peak at one hour, and have a relatively short duration of action (3 to 4 hours). In addition, two long acting insulin analogs have been developed: glargine and detemir, and which may be employed in connection with the invention. The long acting insulin analogs have an onset of action of approximately two hours and reach a plateau of biological action at 4 to 6 hours, and may last up to 24 hours.

Thus, in one embodiment, the insulin component may contain the A and/or B chain of lispro (also known as Humalog, Eli Lilly). Insulin lispro differs from human insulin by the substitution of proline with lysine at position 28 and the substitution of lysine with proline at position 29 of the insulin B chain. Although these modifications do not alter receptor binding, they help to block the formation of insulin dimers and hexamers, allowing for larger amounts of active monomeric insulin to be available for postprandial injections.

In another embodiment, the insulin may contain an A and/or B chain of aspart (also known as Novolog, Novo Nordisk). Insulin aspart is designed with the single replacement of the amino acid proline by aspartic acid at position 28 of the human insulin B chain. This modification helps block the formation for insulin hexamers, creating a faster acting insulin.

In yet another embodiment, the insulin may contain an A and/or B chain of glulisine (also known as Apidra, Sanofi-Aventis). Insulin glulisine is a short acting analog created by substitution of asparagine at position 3 by lysine and lysine at position 29 by glutamine of human insulin B chain. Insulin glulisine has more rapid onset of action and shorter duration of action compared to regular human insulin.

In another embodiment, the insulin may contain an A and/or B chain of glargine (also known as Lantus, Sanofi-Aventis). Insulin glargine differs from human insulin in that the amino acid asparagine at position 21 of the A chain is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Compared with bedtime neutral protamine Hagedorn (NPH) insulin (an intermediate acting insulin), insulin glargine is associated with less nocturnal hypoglycemia in patients with type 2 diabetes.

In yet another embodiment, the insulin may contain an A and/or B chain from detemir (also known as Levemir, Novo Nordisk). Insulin detemir is a soluble (at neutral pH) long-acting insulin analog, in which the amino acid threonine at B30 is removed and a 14-carbon, myristoyl fatty acid is acetylated to the epsilon-amino group of LysB29. After subcutaneous injection, detemir dissociates, thereby exposing the free fatty acid which enables reversible binding to albumin molecules. So at steady state, the concentration of free unbound insulin is greatly reduced resulting in stable plasma glucose levels.

In some embodiments, the insulin may be a single-chain insulin analog (SIA) (e.g. as described in 6,630,438 and WO08/019,368, which are hereby incorporated by reference in their entirety). Single-chain insulin analogs encompass a group of structurally-related proteins wherein the A and B chains are covalently linked by a polypeptide linker. The polypeptide linker connects the C-terminus of the B chain to the N-terminus of the A chain. The linker may be of any length so long as the linker provides the structural conformation necessary for the SIA to have a glucose uptake and insulin receptor binding effect. In some embodiments, the linker is about 5-18 amino acids in length. In other embodiments, the linker is about 9-15 amino acids in length. In certain embodiments, the linker is about 12 amino acids long. In certain exemplary embodiments, the linker has the sequence KDDNPNLPRLVR (SEQ ID NO.: 20) or GAGSSSRRAPQT (SEQ ID NO.: 21). However, it should be understood that many variations of this sequence are possible such as in the length (both addition and deletion) and substitutions of amino acids without substantially compromising the effectiveness of the produced SIA in glucose uptake and insulin receptor binding activities. For example, several different amino acid residues may be added or removed from either end without substantially decreasing the activity of the produced SIA.

An exemplary single-chain insulin analog currently in clinical development is albulin (Duttaroy et al., 2005, Diabetes 54: 251-8). Albulin can be produced in yeast or in mammalian cells. It consists of the B and A chain of human insulin (100% identity to native human insulin) linked together by a dodecapeptide linker and fused to the NH₂ terminals of the native human serum albumin. For expression and purification of albulin, Duttaroy et al. constructed a synthetic gene construct encoding a single-chain insulin containing the B- and A-chain of mature human insulin linked together by a dodecapeptide linker using four overlapping primers and PCR amplification. The resulting PCR product was ligated in-frame between the signal peptide of human serum albumin (HSA) and the NH₂ terminus of mature HSA, contained within a pSAC35 vector for expression in yeast. In accordance with the present invention, the HSA component of abulin may be replaced with an ELP component as described herein.

Thus, in one aspect, the present invention provides therapeutic agents comprising an elastic peptide and an insulin or functional analog thereof. For example, in certain embodiments, the insulin is a mammalian insulin, such as human insulin or porcine insulin. In accordance with the invention, the elastic peptide component may be coupled (e.g., via recombinant fusion or chemical conjugation) to the insulin A chain, or B chain, or both. The insulin may comprise each of chains A, B, and C (SEQ ID NOS: 51 and 52), or may contain a processed form, containing only chains A and B. In some embodiments, chains A and B are connected by a short linking peptide, to create a single chain insulin. The insulin may be a functional analog of human insulin, including functional fragments truncated at the N-terminus and/or C-terminus (of either or both of chains A and B) by from 1 to 10 amino acids, including by 1, 2, 3, or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NOS 15 and 16), and in each case retaining the activity of the peptide. For example, functional analogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (which may contain chains A and B, or chains A, B, and C). Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the insulin component has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with each of the native sequences for chains A and B (SEQ ID NOS:15 and 16). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide sequences, FEMS Microbiol Lett. 174:247-250 (1999). The insulin component may contain additional chemical modifications known in the art.

In another aspect, the present invention provides methods for the treatment or prevention of diabetes, including type I and II diabetes. The method comprises administering an effective amount of the therapeutic agent comprising an elastic peptide (e.g., ELP) component and an insulin (or functional analog thereof) component to a patient in need thereof. Generally, the patient may be a human or non-human animal (e.g., dog, cat, cow, or horse) patient. Preferably, the patient is human.

To characterize the in vitro binding properties of an insulin analog or an elastic peptide-containing insulin analog, competition binding assays may be performed in various cell lines that express the insulin receptor (Jehle et al., 1996, Diabetologia 39: 421-432). For example, competition binding assays using CHO cells overexpressing the human insulin receptor may be employed. Insulin can also bind to the IGF-1 receptor with a lower affinity than the insulin receptor. To determine the binding affinity of an ELP-containing insulin analog, a competition binding assay can be performed using ¹²⁵I-labeled IGF-1 in L6 cells.

The activities of insulin include stimulation of peripheral glucose disposal and inhibition of hepatic glucose production. The ability of an elastic peptide-containing insulin analog to mediate these biological activities can be assayed in vitro using known methodologies. For example, the effect of an elastic peptide-containing analog on glucose uptake in 3T3-L1 adipocytes can be measured and compared with that of insulin. Pretreatment of the cells with a biologically active analog will generally produce a dose-dependent increase in 2-deoxyglucose uptake. The ability of an elastic peptide-containing insulin analog to regulate glucose production may be measured in any number of cells types, for example, H4Ile hepatoma cells. In this assay, pretreatment with a biologically active analog will generally result in a dose-dependent inhibition of the amount of glucose released.

Factor VII (VIIa)

In certain embodiments, the invention provides therapeutic agents comprising an elastic peptide component coupled (e.g., via fusion or conjugation) to a Factor VII/VIIa. Coagulation is the biological process of blood clot formation involving many different serine proteases as well as their essential cofactors and inhibitors. It is initiated by exposure of Factor VII (FVII) and Factor VIIa (FVIIa) to its membrane bound cofactor, tissue factor (TF), resulting in production of Factor Xa (FXa) and more FVIIa. The process is propagated upon production of Factor IXa (FIXa) and additional FXa that, upon binding with their respective cofactors FVIIIa and FVa, form platelet bound complexes, ultimately resulting in the formation of thrombin and a fibrin clot. Thrombin also serves to further amplify coagulation by activation of cofactors such as FV and FVII and zymogens such as Factor XI. Moreover, thrombin activates platelets leading to platelet aggregation, which is necessary for the formation of a hemostatic plug.

Factor VII circulates in the blood in a zymogen form, and is converted to its active form, Factor VIIa, by either factor IXa, factor Xa, factor XIIa, or thrombin by minor proteolysis. Factor VIIa is a two-chain, 50 kilodalton (kDa) plasma serine protease. The active form of the enzyme comprises a heavy chain (254 amino acid residues) containing a catalytic domain and a light chain (152 residues) containing 2 epidermal growth factor (EGF)-like domains. The mature factor VII/VIIa that circulates in plasma is composed of 406 amino acid residues (SEQ ID NO: 33). The light and heavy chains are held together by a disulfide bond.

As noted above, Factor VIIa is generated by proteolysis of a single peptide bond from its single chain zymogen, Factor VII, which is present at approximately 0.5 μg/ml in plasma. The conversion of zymogen Factor VII into the activated two-chain molecule occurs by cleavage of an internal peptide bond. In human Factor VII, the cleavage site is at Arg152-Ile153 (Hagen et al., 1986, PNAS USA 83: 2412-6).

“Factor VII/VIIa” as used in this application means a product consisting of either the unactivated form (factor VII) or the activated form (factor VIIa) or mixtures thereof. “Factor VII/VIIa” within the above definition includes proteins that have an amino acid sequence of native human factor VII/VIIa. It also includes proteins with a slightly modified amino acid sequence, for instance, a modified N-terminal end including N-terminal amino acid deletions or additions so long as those proteins substantially retain the activity of factor VIIa. “Factor VII” within the above definition also includes natural allelic variations that may exist and occur from one individual to another. Also, degree and location of glycosylation or other post-translation modifications may vary depending on the chosen host cells and the nature of the host cellular environment.

In the presence of calcium ions, Factor VIIa binds with high affinity to TF. TF is a 263 amino acid residue glycoprotein composed of a 219 residue extracellular domain, a single transmembrane domain, and a short cytoplasmic domain (Morrissey et al., 1987, Cell 50: 129-35). The TF extracellular domain is composed of two fibronectin type III domains of about 105 amino acids each. The binding of FVIIa is mediated entirely by the TF extracellular domain (Muller et al., 1994, Biochem. 33:10864-70). Residues in the area of amino acids 16-26 and 129-147 contribute to the binding of FVIIa as well as the coagulant function of the molecule. Residues Lys20, Trp45, Asp58, Tyr94, and Phe140 make a large contribution (1 kcal/mol) to the free energy (ΔG) of binding to FVIIa.

TF is expressed constitutively on cells separated from plasma by the vascular endothelium. Its expression on endothelial cells and monocytes is induced by exposure to inflammatory cytokines or bacterial lipopolysaccharides (Drake et al., 1989, J. Cell Biol. 109: 389). Upon tissue injury, the exposed extracellular domain of TF forms a high affinity, calcium dependent complex with FVII. Once bound to TF, FVII can be activated by peptide bond cleavage to yield serine protease FVIIa. The enzyme that catalyzes this step in vivo has not been elucidated, but in vitro FXa, thrombin, TF:FVIIa and FIXa can catalyze this cleavage. FVIIa has only weak activity upon its physiological substrates FX and FIX whereas the TF:FVIIa complex rapidly activates FX and FIX.

The TF:FVIIa complex constitutes the primary initiator of the extrinsic pathway of blood coagulation. The complex initiates the extrinsic pathway by activation of FX to Factor Xa (FXa), FIX to Factor IXa (FIXa), and additional FVII to FVIIa. The action of TF:FVIIa leads ultimately to the conversion of prothrombin to thrombin, which carries out many biological functions. Among the most important activities of thrombin is the conversion of fibrinogen to fibrin, which polymerizes to form a clot. The TF:FVIIa complex also participates as a secondary factor in extending the physiological effects of the contact activation system.

The initiation and subsequent regulation of coagulation is complex, since maintenance of hemostasis is crucial for survival. There is an exquisite balance between hemostasis (normal clot formation and dissolution) and thrombosis (pathogenic clot formation). Serious clinical conditions involving aberrations in coagulation include deep vein thrombosis, myocardial infarction, pulmonary embolism, stroke and disseminated intravascular coagulation (in sepsis). There are also many bleeding coagulopathies where there is insufficient clot formation. These include hemophilia A (FVIII deficiency) or hemophilia B (FIX deficiency), where procoagulant therapy is required. The challenge in this therapeutic area is to operate in the narrow window between too much and too little coagulation.

The use of exogenous FVIIa as a therapeutic agent has been shown to induce hemostasis in patients with hemophilia A and B (Hedner, 2001, Seminars Hematol. 38 (suppl. 12): 43-7; Hedner, 2004, Seminars Hematol. 41 (suppl. 1): 35-9). It also has been used to treat bleeding in patients with liver disease, anticoagulation-induced bleeding, surgery, thrombocytopenia, thrombasthenia, Bemard-Soulier syndrome, von Willebrand disease, and other bleeding disorders (See e.g. Roberts et al., 2004, Blood 104: 3858-64).

Commercial preparations of human recombinant FVIIa are sold as NovoSeven™. NovoSeven™ is indicated for the treatment of bleeding episodes in hemophilia A or B patients and is the only recombinant FVIIa effective for bleeding episodes currently available. A circulating recombinant FVIIa half-life of 2.3 hours was reported in “Summary Basis for Approval for NovoSeven™” FDA reference number 96-0597. Moreover, the half-life of recombinant FVIIa is shorter in pediatric patients (˜1.3 hours), suggesting that higher doses of recombinant FVIIa may be required in this population (Roberts et al., 2004, Blood 104: 3858-64). Accordingly, relatively high doses and frequent administration are necessary to reach and sustain the desired therapeutic or prophylactic effect. As a consequence, adequate dose regulation is difficult to obtain and the need of frequent intravenous administrations imposes restrictions on the patient's way of living.

A molecule with a longer circulation half-life would decrease the number of necessary administrations. Given the frequent injections associated with currently available FVIIa therapy and the potential for obtaining more optimal therapeutic FVIIa levels with concomitant enhanced therapeutic effect, there is a clear need for improved FVII or FVIIa-like molecules with a longer half-life in vivo.

Recombinant human coagulation factor VIIa (rFVIIa, NovoSeven; Novo Nordisk A/S, Copenhagen, Denmark) has proven to be efficacious for the treatment of bleeding episodes in hemophilia patients with inhibitors. A small fraction of patients may be refractory to rFVIIa treatment and could potentially benefit from genetically modified FVIIa molecules with increased potencies. To this end, FVIIa analogs with increased intrinsic activity have been investigated that exhibit superior hemostatic profiles in vitro (see e.g. WO02/077218 or WO05/074975, which are hereby incorporated by reference in their entirety, and Tranholm et al., 2003, Blood 102(10): 3615-20, which is also incorporated by reference). These analogs may also be used as more efficacious hemostatic agents in other indications where efficacy of rFVIIa has been observed, including in thrombocytopenia and trauma.

Thus, in some embodiments, the Factor VIIa analog that may be used in accordance with the invention is as described in WO02/077218 or WO05/074975. For example, the FVIIa analog may have a glutamine substituted for methionine at position 298 (i.e. M298Q-FVIIa). In certain exemplary embodiments, the FVIIa analog contains two additional mutations, valine at position 158 replaced by aspartic acid and glutamic acid at position 296 replaced by valine (i.e. V158D/E296V/M298Q-FVIIa). Additionally or alternatively, the Factor VIIa analog may have an alanine residue substitution for lysine at position 337 (i.e. V158D/E296V/M298Q/K337A-FVIIa). In still other embodiments, the Factor VIIa analog has a substitution or insertion selected from Q250C; P406C; and 407C, wherein a cysteine has also been introduced in the C-terminal sequence (see, e.g. U.S. Pat. No. 7,235,638, which is hereby incorporated by reference in its entirety). The Factor VIIa analog may further comprise a substitution or insertion at one or more of positions 247, 260, 393, 396, and/or 405.

In these or other embodiments, the Factor VIIa analog comprises a substitution relative to the sequence of native Factor VIIa selected from: (a) a substitution of Lys157 with an amino acid selected from the group consisting of Gly, Val, Ser, Thr, Asp, and Glu; (b) a substitution of Lys337 with an amino acid selected from the group consisting of Ala, Gly, Val, Ser, Thr, Gln, Asp, and Glu; (c) a substitution of Asp334 with any amino acid other than Ala or Asn; and (d) a substitution of Ser336 with any amino acid other than Ala or Cys (see e.g. U.S. Pat. No. 7,176,288, which is hereby incorporated by reference in its entirety). Additionally or alternatively, the Factor VIIa analog comprises a substitution of the Leu at position 305 of Factor VII with an amino acid residue selected from the group consisting of Val, Ile, Met, Phe, Trp, Pro, Gly, Ser, Thr, Cys, Tyr, Asn, Glu, Lys, Arg, His, Asp and Gln (see e.g. U.S. Pat. No. 6,905,683, which is hereby incorporated by reference in its entirety).

Thus, in one aspect, the present invention provides therapeutic agents comprising an elastic peptide, e.g., an elastin-like peptide (ELP) and a Factor VII/VIIa, or functional analog thereof. For example, in certain embodiments, the Factor VII/VIIa is human Factor VII/VIIa (e.g., SEQ ID NO: 33). The Factor VII/VIIa may be a functional analog of human Factor VII/VIIa, including functional fragments truncated at the N-terminus and/or C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native sequence (e.g., SEQ ID NO: 33), and in each case retaining the activity of the peptide. For example, such analogs may have from 1 to about 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the native full length sequence, or with respect to one or both of the heavy and light chains. Such activity may be confirmed or assayed using any available assay, including those described herein. In these or other embodiments, the Factor VII/VIIa component has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with the native sequence (SEQ ID NO:33). The determination of sequence identity between two sequences (e.g., between a native sequence and a functional analog) can be accomplished using any alignment tool, including Tatusova et al., Blast 2 sequences—a new tool for comparing protein and nucleotide sequences, FEMS Microbiol Lett. 174:247-250 (1999).

In exemplary embodiments, the FactorVII-ELP fusion has the amino acid sequence of SEQ ID NO:58. SEQ ID NO:58 further comprises a TEV protease cleavage site between the FactorVII and ELP sequences, which may be beneficial for removing the ELP sequence post expression where desired. However, in accordance with the invention, the tev sequence may be entirely removed, or replaced with another linking sequence as disclosed herein.

In another aspect, the present invention provides methods for the treatment or prevention of bleeding-related disorders. The method comprises administering an effective amount of the therapeutic agent comprising an elastic peptide and a Factor VII/VIIa or functional analog thereof to a patient in need. In certain embodiments, the bleeding-related disorder is one or more of hemophilia (A or B), post-surgical bleeding, anticoagulation-induced bleeding, thrombocytopenia, Factor VII deficiency, Factor XI deficiency, bleeding in patients with liver disease, thrombasthenia, Bemard-Soulier syndrome, von Willebrand disease, and intracranial hemorrhage. Generally, the patient is a human or non-human animal (e.g., dog, cat, cow, or horse) patient. Preferably, the patient is human.

To characterize the in vitro binding properties of a suspected Factor VII/VIIa analog, or an elastic peptide-containing Factor VIIa analog, TF binding assays can be performed as described previously (See, e.g., Chaing et al., 1994, Blood 83(12): 3524-35). Briefly, recombinant human TF can be coated onto Immulon II plates in carbonate antigen buffer overnight at 4° C. BSA is also coated onto the plates for use as a control. Elastic peptide-containing Factor VIIa analogs may be added at various concentrations in TBS-T buffer. After several washes, monospecific polyclonal rabbit anti-human FVIIa sera is added and incubated for approximately an hour at room temperature. Next, goat anti-rabbit IgG conjugated to alkaline phosphatase is added, followed by the alkaline phosphatase substrate PNPP, which is used for detection. After subtraction of background, the absorbance at 405 nm is taken to be directly proportional to the degree of Factor VIIa binding to the immobilized TF. These values can then be compared to control plasma containing Factor VIIa.

The clotting ability of a Factor VII/VIIa analog or an elastic peptide-containing Factor VIIa analog can be measured in human FVII deficient plasma. In this assay, the elastic peptide-containing Factor VIIa analog diluted to varying concentrations directly into FVII deficient plasma. In a coagulometer, one part plasma±a FVIIa analog can be mixed with 2 parts Innovin™ (Dade, Miami, Fla.) prothrombin time reagent (recombinant human tissue factor with phospholipids and CaCl₂). Clot formation is detected optically and time to clotting measured. Clotting time (seconds) is compared to the mean clotting time of FVII-deficient plasma alone and plotted as the fractional clotting time versus FVIIa analog concentration.

Therapeutic Proteins

The present invention further provides therapeutic agents comprising an elastic peptide component and at least one therapeutic protein selected from Table 1. The elastic peptide (e.g., ELP) component and therapeutic protein may be coupled by recombinant fusion or chemical conjugation as described herein. Such therapeutic proteins are listed in Table 1 by protein name and GeneSeq Accession No. The amino acid sequence of each Therapeutic Protein, which is known in the art, is hereby incorporated by reference for each Therapeutic Protein listed in Table 1. Such therapeutic proteins are further described in US patent or PCT publications that are also listed in Table 1, and such US patent and PCT publications are hereby incorporated by reference, especially with respect to the structure of such therapeutic proteins and described functional analogs.

Table 1 further describes the biological activity of each listed Therapeutic Protein, as well as an exemplary assay for determining the activity of functional analogs or agents of the invention (e.g., fusion with an elastic peptide component). Generally, functional analogs of therapeutic proteins listed in Table 1 may include functional fragments truncated at the N-terminus and/or C-terminus by from 1 to 10 amino acids, including by 1, 2, 3, 4 or about 5 amino acids. Functional analogs may contain from 1 to 10 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the base sequence (e.g., as listed in Table 1), and in each case retaining the full or partial biological activity (as listed in Table 1) of the therapeutic protein. For example, functional analogs may have 1, 2, 3, 4, or 5 amino acid insertions, deletions, and/or substitutions (collectively) with respect to the base sequence. Such activity may be confirmed or assayed using any available assay, including those described in the Table. In these or other embodiments, the therapeutic protein has at least about 75%, 80%, 85%, 90%, 95%, or 98% identity with the corresponding base sequence. The molecules may further comprise additional chemical modifications known for each in the art.

In some embodiments, the therapeutic protein (e.g., as selected from Table 1) has a size of less than about 25 kDa, or less than about 10 kDa, or less than about 5 kDa, and the corresponding therapeutic agent of the invention (e.g., comprising the ELP component) has a molecular weight of less than about 60 kDa, 55 kDa, 50 kDa, or 40 kDa.

Table 1 further lists preferred indications for each therapeutic protein, for which the corresponding therapeutic agent finds use, such as in a method for treatment or prevention related to such indication.

TABLE 1 Exemplary PCT/Patent Identifier Reference (the (the sequences patents and pub- listed in this lications listed column are each in this column Exemplary Activity Assay hereby are each hereby (the publications listed in this column Therapeutic incorporated by incorporated are each hereby incorporated by Preferred Protein X reference) by reference) Biological Activity reference) Indication Y BMP-1 GeneSeq WO8800205 BMP1 belongs to the transforming BMP-1 activity can be determined Induction of Acession P80618 growth factor-beta (TGFB) super- using the following assays known in Cartilage, Tissue family. Bone morphogenic proteins the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, induce cartilage and bone formation, 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes play important role in nephrogesis, 295-302; J Biol Chem, Vol. 274, Issue and play an important role in the 16, 10897-10902, Apr. 16, 1999; and development of many organs, Hogan, B. L. M. (1996) Genes Dev. including lung, heart, teeth, gut, 10, 1580-1594. skin, and particularly the kidney. BMP-2 GeneSeq WO8800205 BMP-2 belongs to the transforming BMP-2 activity can be determined Induction of Accession P80619 growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-2B GeneSeq U.S. Pat. No. BMP-2b belongs to the transforming BMP-2b activity can be determined Induction of Accession 5,631,142 growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue W24850 superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; I Biol Cbcre, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-4 GeneSeq WO0020591 BMP-4 belongs to the transforming BMP-4 activity can be determined Induction of Accession growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue B02796 superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-5 GeneSeq WO0020591 BMP-5 belongs to the transforming BMP-5 activity can be determined Induction of Accession growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue B02797 superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-6 GeneSeq U.S. Pat. No. BMP-6 belongs to the transforming BMP-6 activity can be determined Induction of Accession 5,187,076 growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue R32904 superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Osteogenic GeneSeq WO973462 OP-1 belongs to the transforming OP-1 activity can be determined using Induction of Protein-1; Accession growth factor-beta (TGFB) the following assays known in the art: Cartilage, Tissue OP-1; BMP-7 W34783 superfamily. Bone morphogenic Nat Genet. 2001 Jan; 27(1): 84-8; Eur J and Bone Growth, protein induces bone formation. Biochem 1996 Apr 1; 237(1): 295-302; and Diabetes J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Osteogenic GeneSeq WO9406399 OP-2 belongs to the transforming OP-2 activity can be determined using Induction of Protein-2 Accession R57973 growth factor-beta (TGFB) the following assays known in the art: Cartilage, Tissue superfamily. Bone morphogenic Nat Genet. 2001 Jan; 27(1): 84-8; Eur J and Bone Growth, protein induces bone formation. Biochem 1996 Apr 1; 237(1): 295-302; and Diabetes J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 0, 1580-1594. GDP-1 GeneSeq WO9406449 Members of the TGF-beta family of The effect of GDF-1 on signaling can Developmental Accession proteins initiate cell signaling by be assayed by treating Primary BAECs disorders, Induction R60961 binding to heteromeric receptor transferred with a construct called of Cartilage, Tissue complexes of type I (TbetaRI) and p3TP-Lux, containing a TGF-beta and Bone Growth, type II (TbetaRII) serine/threonine responsive promoter fused to a reporter and Diabetes kinase receptors (reviewed by gene, and measuring luciferase gene Massague, J. et al. (1994) Trends expression (Wrana et al., 1994, Nature Cell Biol. 4: 172 178; Miyazono, K. 370: 341-347). et al. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg, R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341 347). BMP-9 GeneSeq WO9533830 BMP-9 belongs to the transforming BMP-9 activity can be determined Induction of Accession growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue R86903 superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-10 GeneSeq WO9426893 BMP-10 belongs to the transforming BMP-10 activity can be determined Induction of Accession R66202 growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-12 GeneSeq WO9516035 BMP-12 belongs to the transforming BMP-12 activity can be determined Induction of Accession R78734 growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-15 GeneSeq W09636710 BMP-15 belongs to the transforming BMP-15 activity can be determined Induction of Accession growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue W11261 superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-17 GeneSeq WO9929718 BMP-17 belongs to the transforming BMP-17 activity can be determined Induction of Accession Y17870 growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP-18 GeneSeq WO9929718 BMP-18 belongs to the transforming BMP-18 activity can be determined Induction of Accession Y17871 growth factor-beta (TGFB) using the following assays known in Cartilage, Tissue superfamily. Bone morphogenic the art: Nat Genet. 2001 Jan; 27(1): 84- and Bone Growth, protein induces bone formation. 8; Eur J Biochem 1996 Apr 1; 237(1): and Diabetes 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Inhibin alpha GeneSeq WO0020591 The inhibin beta A subunit joins the Tumor suppressor activity of inhibin Tumor suppression. Accession B02806 alpha subunit to form a pituitary can be determined using assays known FSH secretion inhibitor. Inhibin has in the art: Matzuk et al., Nature 1992 been shown to regulate gonadal Nov. 26: 360 (6402); 313-9. stromal cell proliferation negatively and to have tumour-suppressor activity. In addition, serum levels of inhibin have been shown to reflect the size of granulosa-cell tumors and can therefore be used as a marker for primary as well as recurrent disease. Inhibin beta GeneSeq WO0020591 The inhibin beta A subunit joins the Tumor suppressor activity of inhibin Tumor suppression. Accession alpha subunit to form a pituitary can be determined using assays known H02808 FSH secretion inhibitor. Inhibin has in the art: Matzuk et al., Nature 1992 been shown to regulate gonadal Nov. 26: 360 (6402); 313-9. stromal cell proliferation negatively and to have tumour-suppressor activity. In addition, serum levels of inhibin have been shown to reflect the size of granulosa-cell tumors and can therefore be used as a marker for primary as well as recurrent disease. Cerebus Protein GeneSeq WO9849296 Cerebus is believed to be involved in BMP activity, in the presence of the BMP Antagonist Accession the inhibition of BMP activity antagonist Cerebus, can be determined useful for W86032 using the following assays known in Osteosarcoma, the art: Nat Genet. 2001 Jan; 27(1): 84- abnormal bone 8; Eur J Biochem 1996 Apr 1; 237(1): growth. 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. Soluble BMP GeneSeq WO9614579 Soluble BMP receptor kinase BMP activity, in the presence of the BMP Antagonist Receptor Accession protein-3 is involved in the binding soluble antagonist BMP receptor useful for Kinase Protein- R95227 of BMPs. Soluble BMP receptor kinase protein-3, can be determined Osteosarcoma, 3 kinase protein-3 is useful as an using the following assays known in abnormal bone antagonist for the inhibition of BMP the art: Nat Genet. 2001 Jan; 27(1): 84- growth. activity. 8; Eur J Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274,Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. BMP GeneSeq WO9741250 BMPs belong to the transforming BMP activity, in the presence of the Bone formation or Processing Accession growth factor-beta (TGFB) Furin, can be determined using the Regeneration Enzyme Furin W36099 superfamily. Bone morphogenic following assays known in the art: Nat Abnormalities protein induces bone formation. Genet. 2001 Jan; 27(1): 84-8; Eur J Biochem 1996 Apr 1; 237(1): 295-302; J Biol Chem, Vol. 274, Issue 16, 10897-10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Dev. 10, 1580-1594. TGF-beta 1 GeneSeq WO9216228 Members of the TGF-beta family of The effect of TGF betas on signaling Useful for treating Accession proteins initiate cell signaling by can be assayed by treating Primary cancer and to R29657 binding to heteromeric receptor BAECs transfected with a construct promote wound complexes of type I (TbetaRI) and called p3TP-Lux, containing a TGF- healing. type II (TbetaRII) serine/threonine beta responsive promoter fused to a kinase receptors (reviewed by reporter gene, and measuring luciferase Massague, J. et al. (1994) Trends gene expression (Wrana et al., 1994, Cell Biol. 4: 172 178; Miyazono, K. Nature 370: 341-347). et al. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. TGF-beta 2 GeneSeq EP542679 Members of the TGF-beta family of The effect of TGF betas on signaling Useful for treating Accession proteins initiate cell signaling by can be assayed by treating Primary cancer and to R39659 binding to heteromeric receptor BAECs transfected with a construct promote wound complexes of type I (TbetaRI) and called p3TP-Lux, containing a TGF- healing. type II (TbetaRII) serine/threonine beta responsive promoter fused to a kinase receptors (reviewed by reporter gene, and measuring luciferase Massague, J. et al. (1994) Trends gene expression (Wrana et al., 1994, Cell Biol. 4: 172 178; Miyazono, K. Nature 370: 341-347). et al. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. ZTGF-beta 9 GeneSeq WO0015798 Members of the TGF-beta family of The effect of TGF betas on signaling Useful for treating Accession proteins initiate cell signaling by can be assayed by treating Primary cancer and to Y70654 binding to heteromeric receptor BAECs transfected with a construct promote wound complexes of type I (TbetaRI) and called p3TP-Lux, containing a TGF- healing. type II (TbetaRII) serine/threonine beta responsive promoter fused to a kinase receptors (reviewed by reporter gene, and measuring luciferase Massague, J. et al. (1994) Trends gene expression (Wrana et al., 1994, Cell Biol. 4: 172 178; Miyazono, K. Nature 370: 341-347). et al. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, hich then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. Anti-TGF beta GB2305921 Members of the TGF-beta family of The effect of TGF betas on signaling in Useful for control family proteins initiate cell signaling by the presence of an anti-TGF beta of fibrosis, immune, antibodies binding to heteromeric receptor antibody, can be assayed by treating and inflammatory complexes of type I (TbetaRI) and Primary BAECs transfected with a disease. type II (TbetaRII) serine/threonine construct called p3TP-Lux, containing kinase receptors (reviewed by a TGF-beta responsive promoter fused Massague, J. et al. (1994) Trends to a reporter gene, and measuring Cell Biol. 4: 172 178; Miyazono, K. luciferase gene expression (Wrana et et al. (1994) Adv. Immunol. 55: al., 1994, Nature 370: 341-347). 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. Latent TGF beta GeneSeq WO0012551 Members of the TGF-beta family of The effect of TGF betas on signaling in Useful for binding protein Accession proteins initiate cell signaling by the presence of a TGF beta binding inhibiting tissue or II Y70552 binding to heteromeric receptor protein, can be assayed by treating tumor growth. complexes of type I (TbetaRI) and Primary BAECs transfected with a type II (TbetaRII) serine/threonine construct called p3TP-Lux, containing kinase receptors (reviewed by a TGF-beta responsivepromoter fused Massague, J. et al. (1994) Trends to a reporter gene, and measuring Cell Biol. 4: 172 178; Miyazono, K. luciferase gene expression (Wrana et et al. (1994) Adv. Immunol. 55: al., 1994, Nature 370: 341-347). 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. MP52 GeneSeq WO9741250 Members of the TGF-beta family of The effect of TGF betas on signaling Bone formation or Accession proteins initiate cell signaling by can be assayed by treating Primary Regeneration W36100 binding to heteromeric receptor BAECs transfected with a construct Abnormalities complexes of type I (TbetaRI) and called p3TP-Lux, containing a TGF- type II (TbetaRII) serine/threonine beta responsive promoter fused to a kinase receptors (reviewed by reporter gene, and measuring luciferase Massague, J. et al. (1994) Trends gene expression (Wrana et al., 1994, Cell Biol. 4: 172 178; Miyazono, K. Nature 370: 341-347). et al. (1994) Adv. Immunol. 55: 181-220). Activation of this heteromeric receptor complex occurs when TGF-beta. binds to TbetaRII, which then recruits and phosphorylates TbetaRI. Activated TbetaRI then propagates the signal to downstream targets (Chen, F. and Weinberg. R. A. (1995) PNA892: 1565-1569; Wrana, J. L. et al. (1994) Nature 370: 341. b57 Protein GeneSeq WO9837195 BMPs are involved in the induction BMP activity, in the presence of b57 BMP Antagonist Accession of bone formation. Specific protein, can be determined using the useful for W69293 antagonists are useful is preventing following assays known in the art: Nat Osteosarcoma, this activity from occurring. Genet. 2001 Jan; 27(1): 84-8; Eur J abnormal bone Biochem 1996 Apr 1; 237(1): 295-302; growth. J Biol Chem, Vol. 274, Issue 16, 1089- 10902, Apr. 16, 1999; and Hogan, B. L. M. (1996) Genes Deve. 10, 1580- 1594. Resistin GeneSeq WO0064920 This gene belongs to the family Ability of resistin to influence type II Type II diabetes Accession defined by mouse FIZZI and diabetes can be determined using and Syndrome X. W69293 FIZZ3/Resistin genes. The assays known in the art: Pontoglio et characteristic feature of this family al., J Clin Invest 1998 May 15; is the C-terminal stretch of 10 cys 101(10): 2215-22. residues with identical spacing. The mouse homolog of this protein is secreted by adipocytes, may be the hormone potantially linking obesity to type II diabetes. Galectin-4 GeneSeq WO9703190 Galectins are a family of Ability of Galectin-4 polypeptides to Lactose intolerance. Accession carbohydrate-binding proteins bind lactose can be determined using W11841 characterized by an affinity for beta- assays known in the art: Wada, et al., J galactoside containing Biol Chem 1997 Feb 28; 272(9): 6078- glycoconjugates. 86. APM-I; ACRP- GeneSeq W00026363 ACPR30 gene is exclusively Ability of ACRP30 polypeptides to Obesity, Metabolic 30; Famoxin Accession expressed in adipose tissue. influence obesity and fat oxidation can disorders, Lipid Y71035 ACRP30 is thought to increase fatty be determined using assays known in Metabolism; acid oxidation by muscle tissue. the art: Fruebis et al., Proc Nat'l Acad Hormone Secretion. Sci USA 2001 Feb 13; 98(4): 2005-10. ACRP-30 GeneSeq WO0063376 ACPR30 gene is exclusively Ability of ACRP30 homologue Obesity, Metabolic Homologue; Accession expressed in adipose tissue. polypeptides to influence obesity and disorders, Lipid Complement B30234 ACRP30 is thought to increase fatty fat oxidation can be determined using Metabolism; Component Clq acid oxidation by muscle tissue. assays known in the art: Fruebis et al., Hormone Secretion. C Proc Nat'l Acad Sci USA 2001 Feb 13; 98(4): 2005-10. Calpain-10a GeneSeq WO0023603 Calpain is believed to play a role in Ability of Calpain-10 to influence type Diabetes mellitus; Accession insulin secretion and insulin activity, II diabetes can be determined using Regulation of Y79567 and therefore may be useful in the assays known in the art: Pontoglio et Insulin secretory treatment of type II diabetes. al., J Clin Invest 1998 May 15; response; Insulin 101(10): 2215-22. mediated glucose transport disorders. Calpain-10b GeneSeq WO0023603 Calpain is believed to play a role in Ability of Calpain-10 to influence type Diabetes mellitus; Accession insulin secretion and insulin activity, II diabetes can be determined using Regulation of Y79568 and therefore may be useful in the assays known in the art: Pontoglio et Insulin secretory treatment of type II diabetes. al., J Clin Invest 1998 May 15; response; Insulin 101(10): 2215-22. mediated glucose transport disorders. Calpain-10c GeneSeq WO0023603 Calpain is believed to play a role in Ability of Calpain-10 to influence type Diabetes mellitus; Accession insulin secretion and insulin activity, II diabetes can be determined using Regulation of Y79569 and therefore may be useful in the assays known in the art: Pontoglio et Insulin secretory treatment of type II diabetes. al., J Clin Invest 1998 May 15; response; Insulin 101(10): 2215-22. mediated glucose transport disorders. PDGF-D GeneSeq WO0027879 Vascular Endothelial Growth Factor. Proliferation assay using NR6R-3T3 Wound Healing; Accession cells (Rizzino 1988 Cancer Res. 48: Atherosclermis. Y71130 4266). FasL GeneSeq WO9936079 Activities associated with apoptosis Activity can be determined using Apoptosis-related Accession and immune system functions. Apoptosis assays known in the art: disorders; Auto- Y28594 Walczak et al. (1996) EMBOJ 16: immune disorders; 5386-5397. Graft v-Host disorders. Chondro GeneSeq W00029579 Chondromodulin proteins are Ability of Chondromodulin-like Antianglogenic modulin-like Accession cartilage proteins thought to confer protein to inhibit vascularization can be agent; Osteoblast protein Y71262 resistance to anglogeneis, and thus determined using assays known in the proliferation are useful as anti-angiogenic agents art: Hirakie et al., J Biol Chem 1997 stimulator; prevents that may have utility in combating Dec 19; 272(51): 32419-26. vascularization of cancer. cartilage tissue; Useful to treat cancer. Patched GeneSeq U.S. Pat. No. Patched is a tumour-suppressor Ability of soluble Patched to bind to Receptor for Accession 5,837,538 receptor for Sonic hedgehog (shh), and inhibit the activities of shh can be Hedgehog cellular W72969 which is a protein that controls determined using assays known in the proliferation developmental patterning and art: Stone et al., Nature 1996 Nov 14; signaling molecule. growth. 384(6605): 129-34. This receptor is useful as a means of preventing cellular proliferation via the shh signaling path- way, thus useful for cancers. Patched-2 GeneSeq WO9953058 Patched is a tumour-suppressor Ability of soluble Patched to bind to Receptor for Accession receptor for Sonic hedgehog (shh), and inhibit the activities of shh can be Hedgehog cellular Y43261 which is a protein that controls determined using assays known in the proliferation developmental patterning and art: Stone et al., Nature 1996 Nov 14; signaling molecule. growth. 384(6605): 129-34. This receptor is useful as a means of preventing cellular proliferation via the shh signaling path- way, thus useful for cancers. Maspin; GeneSeq WO9405804 Maspin is a member of the serpin The inhibitory effects cf Maspin and Tumor suppressor Protease Accession family of serine protease inhibitors other protease inhibitors can be which is down- Inhibitor 5 R50938 that is thought to suppress tumor assayed using methods known in the regulated in breast metastasis. art such as a labeled protease substrate, cancers. The for example, Universal Protease maspin protein has Substrate (casein, resorufin-labeled): tumour suppressing Roche Molecular Biochemicals, Cat. and invasion sup- No. 1080733. pressing activity. Endostatin GeneSeq WO0064946 Endostatin is believed to inhibit The inhibitory effects of endostatin can Anti-angiogenic Accession effects of capillary endothelial cell be assayed using assays disclosed by activity. Useful in B28399 proliferation. Cao et al. (1996) J. Biol. Chem. 271 the prevention and/ 29461-29467. or treatment of cancers. aFGF; FGF-1 GeneSeq EP298723 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- P94037 4266); Examples 23 and 39 disclosed eration of cells, herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. bFGF; FGF-2 GeneSeq FR2642086 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- R06685 4266); Examples 23 and 39 disclosed eration of cells, herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. FGF-3; INT-2 GeneSeq WO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- R07824 4266); Examples 23 and 39 disclosed eration of cells, herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. FGF-4; HST-1; GeneSeq WO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of HBGF-4 Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- R07825 4266); Examples 23 and 39 disclosed eration of cells, herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. FGF-5 GeneSeq WO9730155 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- W22600 4266); Examples 23 and 39 disclosed eration of cells, herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. FGF-6; Heparin GeneSeq EP613946 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of binding secreted Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- transforming R58555 4266); Examples 23 and 39 disclosed eration of cells, factor-2 herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. FGF-8 GeneSeq WO9524928 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- R80783 4266); Examples 23 and 39 disclosed eration of cells, herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. FGF-9; Gila GeneSeq WO9503831 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of activating factor Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- R70822 4266); Examples 23 and 39 disclosed eration of cells, herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. FGF-12; GeneSeq WO9635708 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of Fibroblast Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- growth factor W06309 4266); Examples 23 and 39 disclosed eration of cells, homologous herein. such as epithelial factor-1 cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. FGF-15 GeneSeq WO9927100 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- Y08582 4266); Examples 23 and 39 disclosed eration of cells, herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. FGF-16 GeneSeq WO9918128 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- Y05474 4266); Examples 23 and 39 disclosed eration of cells, herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. FGF-18 GeneSeq WO9927100 Fibroblast Growth Factor Proliferation assay using NR6R-3T3 Promotion of Accession cells (Rizzino 1988 Cancer Res. 48: growth and prolif- Y08590 4266); Examples 23 and 39 disclosed eration of cells, herein. such as epithelial cells and keratino- cytes. Antagonists may be useful as anti-cancer agents. fit-3 ligand GeneSeq EP627487 Stem Cell Progenitor Chemokine activities can be Promotion of Accession determined using assays known in the immune cell growth R67541 art: Methods in Molecular Biology, and/or 2000, vol. 138: Chemokine Protocols. differentiation. Edited by: A. E. I. Proudfoot, T. N. C. Wells, and C. A. Power. © Humana Press Inc., Totowa, NJ. VEGF-110 GeneSeq WO0013702 Promotes the growth and/or VEGF activity can be determined using Promotion of growth Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of Y69417 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGB-121 GeneSeq WO0071713 Promotes the growth and/or VEGF activity can be determined using Promotion of growth Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of B50432 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-138 GeneSeq WO9940197 Promotes the growth and/or VEGF activity can be determined using Promotion of growth Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of Y43483 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-145 GeneSeq WO0013702 Promotes the growth and/or VEGF activity can be determined using Promotion of growth Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of Y69413 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-162 GeneSeq W09940197 Promotes the growth and/or VEGF activity can be determined using Promotion of growth Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of Y43484 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-165 GeneSeq WO0013702 Promotes the growth and/or VEGF activity can be determined using Promotion of growth Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of Y69414 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-182 GeneSeq W09940197 Promotes the growth and/or VEGF activity can be determined using Promotion of growth Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of Y43483 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-189 GeneSeq WO0013702 Promotes the growth and/or VEGF activity can be determined using Promotion of growth Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of Y69415 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-206 GeneSeq W00013702 Promotes the growth and/or VEGF activity can be determined using Promotion of growth Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of Y69416 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-D GeneSeq WO9807832 Promotes the growth and/or VEGF activity can be determined using Promotion of growth Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of W53240 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF-E; GeneSeq W09947677 Promotes the growth and/or VEGF activity can be determined using Promotion of growth VEGF-X Accession proliferation of endothelial cells. assays known in the art, such as those and proliferation of Y33679 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. VEGF GeneSeq WO9831794 Receptor for VEGF polypeptides VEGF activity, in the presence of flk-1 VEGF Receptor. Receptor; KDR; Accession polypeptides, can be determined using Fusion protein with flk-1 W69679 assays known in the art, such as those the extracellular disclosed in International Publication domain is useful as No. WO0045835, for example. an anti-angiogenic agent. Antagonists may be useful in the promotion of angiogenesis. Soluble VEGF GeneSeq U.S. Pat. No. Receptor for VEGF polypeptides VEGF activity, in the presence of VEGF Receptor. Receptor Accession 5,712,380 VEGF Receptor polypeptides, can be Fusion protein with W47037 determined using assays known in the the extracellular art, such as those disclosed in domain is useful as International Publication No. an anti-angiogenic WO0045835, for example. agent. Antagonists may be useful in the promotion of angiogenesis. flt-1 GeneSeq WO0021560 Receptor for VEGF polypeptides VEGF activity, in the presence of flt-1 VEGF Receptor. Accession polypeptides, can be determined using Fusion protein with Y70751 assays known in the art, such as those the extracellular disclosed in International Publication domain is useful as No. WO0045835, for example. an anti-angiogenic agent. Antagonists may be useful in the promotion of angiogenesis. VEGF R-3; flt-4 GeneSeq WO0058511 Receptor for VEGF polypeptides VEGF activity, in the presence of flt-4 VEGF Receptor. Accession polypeptides, can be determined using Fusion protein with B29047 assays known in the art, such as those the extracellular disclosed in International Publication domain is useful as No. WO0045835, for example. an anti-angiogenic agent. Antagonists may be useful in the promotion of angiogenesis. Neuropilin-1 GeneSeq WO9929858 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth Accession assays known in the art, such as those and proliferation of Y06319 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Neuropilin-2 GeneSeq WO9929858 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth Accession assays known in the art, such as those and proliferation of Y03618 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Human fast GeneSeq W09730085 Troponins are contractile proteins Ability of soluble Troponins to inhibit Anti-angiogenesis twitch skeletal Accession that are thought to inhibit angio- anglogenesis can be determined using muscle troponin W22597 gencsis. High levels may contribute assays known in the art:. Proc Natl C to the difficulty encountered in Acad Sci USA 1999 Mar 16; 96(6): revascularizing the ischemic myo- 2645-50. cardium after cardiovascular injury. Human fast GeneSeq W09730085 Troponins are contractile proteins Ability of soluble Troponins to inhibit Anti-angiogenesis twitch skeletal Accession that are thought to inhibit angio- anglogenesis can be determined using muscle troponin W18054 gencsis. High levels may contribute assays known in the art:. Proc Natl I to the difficulty encountered in Acad Sci USA 1999 Mar 16; 96(6): revascularizing the ischemic myo- 2645-50. cardium after cardiovascular injury. Human fast GeneSeq W09730085 Troponins are contractile proteins Ability of soluble Troponins to inhibit Anti-angiogenesis twitch skeletal Accession that are thought to inhibit angio- anglogenesis can be determined using muscle troponin W22599 gencsis. High levels may contribute assays known in the art:. Proc Natl T to the difficulty encountered in Acad Sci USA 1999 Mar 16; 96(6): revascularizing the ischemic myo- 2645-50. cardium after cardiovascular injury. fragment. GeneSeq W09719955 Troponins are contractile proteins Ability of soluble Troponins to inhibit Anti-angiogenesis myofibrillar Accession that are thought to inhibit angio- anglogenesis can be determined using protein troponin W18053 gencsis. High levels may contribute assays known in the art:. Proc Natl I to the difficulty encountered in Acad Sci USA 1999 Mar 16; 96(6): revascularizing the ischemic myo- 2645-50. cardium after cardiovascular injury. myofibrillar GeneSeq W09719955 Troponins are contractile proteins Ability of soluble Troponins to inhibit Anti-angiogenesis protein troponin Accession that are thought to inhibit angio- anglogenesis can be determined using I W18054 gencsis. High levels may contribute assays known in the art:. Proc Natl to the difficulty encountered in Acad Sci USA 1999 Mar 16; 96(6): revascularizing the ischemic myo- 2645-50. cardium after cardiovascular injury. Troponin GeneSeq WO9933874 Troponins are contractile proteins Ability of soluble Troponins to inhibit Anti-angiogenesis peptides Accessions that are thought to inhibit angio- anglogenesis can be determined using Y29581, Y29582, gencsis. High levels may contribute assays known in the art:. Proc Natl Y29583, Y29584, to the difficulty encountered in Acad Sci USA 1999 Mar 16; 96(6): Y29585, and revascularizing the ischemic myo- 2645-50. Y29586 cardium after cardiovascular injury. Human fast GeneSeq WO0054770 Troponins are contractile proteins Ability of soluble Troponins to inhibit Anti-angiogenesis twitch skeletal Accession that are thought to inhibit angio- anglogenesis can be determined using muscle B00134 gencsis. High levels may contribute assays known in the art:. Proc Natl Troponin to the difficulty encountered in Acad Sci USA 1999 Mar 16; 96(6): subunit C revascularizing the ischemic myo- 2645-50. cardium after cardiovascular injury. Human fast GeneSeq WO0054770 Troponins are contractile proteins Ability of soluble Troponins to inhibit Anti-angiogenesis twitch skeletal Accession that are thought to inhibit angio- anglogenesis can be determined using muscle B00135 gencsis. High levels may contribute assays known in the art:. Proc Natl Troponin to the difficulty encountered in Acad Sci USA 1999 Mar 16; 96(6): subunit I revascularizing the ischemic myo- 2645-50. Protein cardium after cardiovascular injury. Human fast GeneSeq WO0054770 Troponins are contractile proteins Ability of soluble Troponins to inhibit Anti-angiogenesis twitch skeletal Accession that are thought to inhibit angio- anglogenesis can be determined using muscle B00136 gencsis. High levels may contribute assays known in the art:. Proc Natl Troponin to the difficulty encountered in Acad Sci USA 1999 Mar 16; 96(6): subunit T revascularizing the ischemic myo- 2645-50. cardium after cardiovascular injury. Activator GeneSeq WO9013648 PAIs are believed to play a role in Methods that measure plasminogen Anti-angiogenesis; Inbibitor-1; Accession cancer, and cardiovascular disease activator inhibitor (PAI) activity are blood-clotting PAI-1 R08411 and blood-clotting disorders. known in the art, for example, assay the disorders. ability of PAI to inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti- angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar 16; 96(6): 2645-50. Plasminogen GeneSeq DE3722673 PAIs are believed to play a role in Methods that measure plasminogen Anti-angiogenesis; Activator Accession cancer, and cardiovascular disease activator inhibitor (PAI) activity are blood-clotting Inhibitor-2; P94160 and blood-clotting disorders. known in the art, for example, assay the disorders. PAI-2 ability of PAI to inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti- angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar 16; 96(6): 2645-50. Activator GeneSeq WO9102057 PAIs are believed to play a role in Methods that measure plasminogen Anti-angiogenesis; Inhibitor-2; Accession cancer, and cardiovascular disease activator inhibitor (PAI) activity are blood-clotting PAI-2 R10921 and blood-clotting disorders. known in the art, for example, assay the disorders. ability of PAI to inhibit tissue plasminogen activator (tPA) or urokinase (uPA): J Biochem Biophys Methods 2000 Sep 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti- angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar 16; 96(6): 2645-50. Human PAI-1 GeneSeq WO9105048 PAIs are believed to play a role in Methods that measure plasminogen Anti-angiogenesis; mutants Accessions cancer, and cardiovascular disease activator inhibitor (PAI) activity are blood-clotting R11755, R11756, and blood-clotting disorders. known in the art, for example, assay the disorders. R11757, R11758, ability of PAI to inhibit tissue R11759, R11760, plasminogen activator (tPA) or R11761, R11762 urokinase (uPA): J Biochem Biophys and R11763 Methods 2000 Sep 11; 45(2): 127-40, Breast Cancer Res Treat 1996; 41(2): 141-6. Methods that measure anti- angiogenesis activity are known in the art, for example, Proc Natl Acad Sci USA 1999 Mar 16; 96(6): 2645-50. CXCR3; CXC GeneSeq WO0018431 Chemokines are a family of related Chemokine activities can be determined Soluble CXCR3 Accession small, secreted proteins involved in using assays known in the art: Methods polypeptides may be Y79372 biological processes ranging from in Molecular Biology, 2000, vol. 138: useful for inhibiting hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. chemokine activities leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and viral infection. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Modified GeneSeq WO9737005 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Rantes Accession small, secreted proteins involved in using assays known in the art: Methods W38129 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES GeneSeq EP905240 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods Y05299 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCI-Ia GeneSeq WO9509232 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods R73914 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-Ib GeneSeq WO9929728 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods Y26176 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-I receptor GeneSeq WO9519436 Chemokines are a family of related Chemokine activities can be determined Soluble MCP-1 Accession small, secreted proteins involved in using assays known in the art: Methods Receptor polypep- R79165 biological processes ranging from in Molecular Biology, 2000, vol. 138: tides may be useful hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. for inhibiting leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. chemokine activities this family are involved in a Power. and viral infection. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-3 GeneSeq W09509232 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods R73915 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. MCP-4 receptor GeneSeq W09809171 Chemokines are a family of related Chemokine activities can be determined Soluble MCP-4 Accession small, secreted proteins involved in using assays known in the art: Methods Receptor polypep- W56689 biological processes ranging from in Molecular Biology, 2000, vol. 138: tides may be useful hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. for inhibiting leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. chemokine activities this family are involved in a Power. and viral infection. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Soluble RANTES receptor Accession 5,652,133 small, secreted proteins involved in using assays known in the art: Methods Receptor polypep- W29588 biological processes ranging from in Molecular Biology, 2000, vol. 138: tides may be useful hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. for inhibiting leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. chemokine activities this family are involved in a Power. and viral infection. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CCR5 variant GeneSeq WO9854317 Chemokines are a family of related Chemokine activities can be determined Soluble CCR5 Accession small, secreted proteins involved in using assays known in the art: Methods polypeptides may be W88238 biological processes ranging from in Molecular Biology, 2000, vol. 138: useful for inhibiting hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. chemokine activities leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and viral infection. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CCR7 GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Soluble CCR7 Accession 6,153,441 small, secreted proteins involved in using assays known in the art: Methods polypeptides may be B50859 biological processes ranging from in Molecular Biology, 2000, vol. 138: useful for inhibiting hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. chemokine activities leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and viral infection. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CXC3 GeneSeq WO9727299 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods W23345 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Eotaxin GeneSeq WO9700960 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods W10099 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Neurotactin GeneSeq U.S. Pat. No. Neurotactin may play a role in Chemotactic leukocyte migration assays Immune disorders. Accessions 6,013,257 chemotactic leukocyte migration and are known in the art, for example: J. Y77537, W34307, WO9742224 brain inflammation processes. Immunol. Methods 33, ((1980)); Nature Y53259, and, 1997 Jun 5; 387(6633): 611-7. Y77539 Human GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Immune disorders. CKbeta-9 Accession 6,153,441 small, secreted proteins involved in using assays known in the art: Methods B50860 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G- protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Lymphotactin GeneSeq WO0073320 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods B50052 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G. MIP-3 alpha GeneSeq WO9801557 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods W44398 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G. MIP-3 beta GeneSeq WO9801557 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods W44399 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G. MIP-Gamma GeneSeq WO9504158 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods R70798 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G. Stem Cell GeneSeq WO9104274 Chemokines are a family of related Chemokine activities can be determined Hematopoietic Inhibitory Accession small, secreted proteins involved in using assays known in the art: Methods growth factors. Factor R11553 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a Power. similarly diverse range of patholo- © Humana Press Inc., Totowa, NJ. gies including inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G. thrombopoietin GeneSeq WO9521920 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed Hematopoietic Accession regulation of the growth and to determine regulation of growth and growth factors. R79905 differentiation of megakaryocytes differentiation of megakaryocytes. Mol and preceptors thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. c-kit ligand; GeneSeq EP992579 and C-kit ligan is thought to stimulate Chemokine activities can be determined Hematopoietic SCF; Mast cell Accession EP676470 the proliferation of mast cells, and is using assays known in the art: Methods growth factors. growth factor; Y53284, R83978 able to augment the proliferation of in Molecular Biology, 2000, vol. 138: MGF; and R83977 both myeloid and lymphoid hemato- Chemokine Protocols. Edited by: A. E. Fibrosarcoma- poietic progenitors in bone marrow I. Proudfoot, T. N. C. Wells, and C. A. derived stem culture. C-kit ligand is also though Power. cell factor to act synergistically with other © Humana Press Inc., Totowa, NJ. cytokines. Platelet derived GeneSeq WO0066736 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth growth factor Accession B48653 assays known in the art, such as those and proliferation of disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Melanoma GeneSeq WO9503328 Melanoma inhibiting protein has Tumor suppressor activity of melanoma Cancer; melanoma inhibiting Accession R69811 melanoma-inhibiting activity and inhibiting protein can be determined protein can be used to treat cancer using assays known in the art: Matzuk (melanoma, glioblastoma, neuro- et al., Nature 1992 Nov 26; 360(6402): blastoma, small cell lung cancer, 313-9. neuroectodermal tumors) or as an immunosuppressant (it inhibits IL-2 or phytohaemagglutinin induced proliferation of peripheral blood lymphocytes. Glioma-derived GeneSeq EP399816 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth growth factor Accession R08120 assays known in the art, such as those and proliferation of disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Platelet derived GeneSeq EP682110 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth growth factor Accession R84759 assays known in the art, such as those and proliferation of precursor A disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Platelet derived GeneSeq EP682110 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth growth factor Accession R84760 assays known in the art, such as those and proliferation of precursor B disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Platelet derived GeneSeq EP282317 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth growth factor Accession P80595 assays known in the art, such as those and proliferation of Bvsis and P80596 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Placental GeneSeq WO9206194 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth Growth Factor Accessions assays known in the art, such as those and proliferation of R23059 and disclosed in International Publication cells, such as R23060 No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Placental GeneSeq DE19748734 Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth Growth Factor- Accession Y08289 assays known in the art, such as those and proliferation of 2 disclosed in International Publication cells, such as No. WO0045835, for example. vascular endothelial cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed Thrombocytopenia, derivative1 Accession Y77244 regulation of the growth and to determine regulation of growth and cancer. differentiation of megakaryocytes differentiation of megakaryocytes. Mol and preceptors thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed Thrombocytopenia, derivative2 Accession Y77255 regulation of the growth and to determine regulation of growth and cancer. differentiation of megakaryocytes differentiation of megakaryocytes. Mol and preceptors thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed Thrombocytopenia, derivative3 Accession Y77262 regulation of the growth and to determine regulation of growth and cancer. differentiation of megakaryocytes differentiation of megakaryocytes. Mol and preceptors thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed Thrombocytopenia, derivative4 Accession Y77267 regulation of the growth and to determine regulation of growth and cancer. differentiation of megakaryocytes differentiation of megakaryocytes. Mol and preceptors thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed Thrombocytopenia, derivative5 Accession Y77246 regulation of the growth and to determine regulation of growth and cancer. differentiation of megakaryocytes differentiation of megakaryocytes. Mol and preceptors thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed Thrombocytopenia, derivative6 Accession Y77253 regulation of the growth and to determine regulation of growth and cancer. differentiation of megakaryocytes differentiation of megakaryocytes. Mol and preceptors thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Thrombopoietin GeneSeq WO0000612 Thrombopoietin is involved in the Thrombopoietin (TPO) can be assayed Thrombocytopenia, derivative7 Accession Y77256 regulation of the growth and to determine regulation of growth and cancer. differentiation of megakaryocytes differentiation of megakaryocytes. Mol and preceptors thereof. Cell Biol 2001 Apr; 21(8): 2659-70; Exp Hematol 2001 Jan; 29(1): 51-8 and within. Fractalkine GeneSeq U.S. Pat. No. Fractalkine is believed to play a role Fractalkine activity can be determined Immune disorders. Accession Y53255 6,043,086 in chemotactic leukocyte migration using Chemotactic leukocyte migration and neurological disorders. assays known in the art, for example: J. Immunol. Methods 33, ((1980)); Nature 1997 Jun 5; 387(6633): 611-7. CXC3 GeneSeq WO9757599 Chemokines are a family of related Chemokine activities can be determined Immune disorders. Accession small, secreted proteins involved in using assays known in the art: Methods W23345 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. CCR7 GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Soluble CCR7 Accession B50859 6,153,441 small, secreted proteins involved in using assays known in the art: Methods polypeptides may be biological processes ranging from in Molecular Biology, 2000, vol. 138: useful for inhibiting hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. chemokine activities leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and viral infection. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Nerve Growth GeneSeq EP414151 Nerve Growth Factor Proliferation assay using NR6R-3T3 Neurological Factor-beta Accession R11474 cells (Rizzino 1988 Cancer Res. 48: disorders, cancer 4266) Nerve Growth GeneSeq EP859056 Nerve Growth Factor Proliferation assay using NR6R 3T3 Neurological Factor-beta2 Accession cells (Rizzino 1988 Cancer Res. 48: disorders, cancer W69725 4266 Neurotrophin-3 GeneSeq WO9821234 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological Accession survival and synaptic plasticity. known in the art can be used to assay disorders, cancer W8889 for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin-3 GeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological Accession R47100 survival and synaptic plasticity. known in the art can be used to assay disorders, cancer for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin- GeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological 4a Accession R47101 survival and synaptic plasticity. known in the art can be used to assay disorders, cancer for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin- GeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological 4b Accession R47102 survival and synaptic plasticity. known in the art can be used to assay disorders, cancer tyrosine kinases. for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin- GeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological 4c Accession R47103 survival and synaptic plasticity. known in the art can be used to assay disorders, cancer tyrosine kinases. for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Neurotrophin- GeneSeq WO9325684 Neurotrophins regulate neuronal cell Trk tyrosine kinase activation assays Neurological 4d Accession R47102 survival and synaptic plasticity. known in the art can be used to assay disorders, cancer tyrosine kinases. for neurotrophin activity, for example, Proc Natl Acad Sci USA 2001 Mar 13; 98(6): 3555-3560. Platelet-Derived GeneSeq U.S. Pat. No. Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth Growth Factor Accession R38918 5,219,739 assays known in the art, such as those and proliferation of A chain disclosed in International Publication cells, such as No. W00045835, for example. vascular endothelial cells. Hematopoietic and immune dis- orders. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer Platelet-Derived GeneSeq U.S. Pat. No. Vascular Endothelial Growth Factor VEGF activity can be determined using Promotion of growth Growth Factor Accession R38919 5,219,739 assays known in the art, such as those and proliferation of B chain disclosed in International Publication cells, such as No. W00045835, for example. vascular endothelial cells. Hematopoietic and immune dis- orders. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer Stromal GeneSeq WO9948528 Stromal Growth Factor Proliferation assay using NR6R-3T3 Hematopoietic, Derived Factor- Accession cells (Rizzino 1988 Cancer Res. 48: immune disorders, 1 alpha Y39995 4266) cancer Stromal GeneSeq CA2117953 Stromal Growth Factor Proliferation assay using NR6R-3T3 Hematopoietic, Derived Factor- Accession cells (Rizzino 1988 Cancer Res. 48: immune disorders, 1 beta R75420 4266) cancer Tarc GeneSeq WO9711969 Chemotactic for T lymphocytes. Chemotactic leukocyte migration assays Antiinflammatory. Accession May play a role in T-cell develop- are known in the art, for example: J. Immune disorders, W14917 ment. Thought to bind CCR8 and Immunol. Methods 33 ((1980)) cancer CCR4 Prolactin GeneSeq WO9521625 Prolactin is involved in immune cell Immune coil proliferation and Reproductive system Accession R78691 proliferation and apoptosis. suppression of apoptosis by prolactin disorders, cancer. can be assayed by methods well-known in the art, for example, Buckley, AR and Buckley DJ, Ann N Y Acad Sci 2000; 917: 522-33, and within. Prolactin2 GeneSeq U.S. Pat. No. Prolactin is involved in immune cell Immune coil proliferation and Reproductive system Accession 5,955,346 proliferation and apoptosis. suppression of apoptosis by prolactin disorders, cancer. Y31764 can be assayed by methods well-known in the art, for example, Buckley, AR and Buckley DJ, Ann N Y Acad Sci 2000; 917: 522-33, and within. Follicle GeneSeq EP974359 FSH stimulates secretion of FSH activities can be determined using Reproductive system stimulating Accession interleukin-1 by cells isolated from assays known in the art; J Gend Specif disorders, cancer. hormone Alpha Y54160 women in the follicular phase Med 1999 Nov-Dec; 2(6): 30-4; Mol subunit Cell Endocrinol. 1997 Nov 15; 134(2): 109-18. Follicle GeneSeq EP974359 FSH stimulates secretion of FSH activities can be determined using Reproductive system stimulating Accession interleukin-1 by cells isolated from assays known in the art; J Gend Specif disorders, cancer. hormone Beta Y54161 women in the follicular phase Med 1999 Nov-Dec; 2(6): 30-4; Mol subunit Cell Endocrinol. 1997 Nov 15; 134(2): 109-18. Substance P GeneSeq WO0054053 Substance P is associated with Immuneregulation and bone marrow, diabetes mellitus, (tachykinin) Accession immunoregulation. cell proliferation by substance P can be hypertension, cancer B23027 assayed by methods well-known in the art, for example, Lai et al. Proc Natl Acad Sci USA 2001 Mar 27; 98(7): 3970-5; Jallat-Daloz et al. Allergy Asthma Proc 2001 Jan-Feb; 22(1): 17- 23; Kahler et al. Exp Lung Res 2001 Jan-Feb; 27(1): 25-46; and Adamus MA and Dabrowski ZJ. J Cell Biochem 2001; 81(3)499-506. Ocytocin GeneSeq WO0053755 Oxytocin is involved in the Oxytocin and prostaglandin E(2) inflammatory (Neurophysin I) Accession induction of prostaglandin (E2) release and Ocytocin (Ca2+) increase disorders B24085 and release as well as an increased can be assayed by methods well-known immunologic B24086 amount of calcium release by in the art, for example, Pavan et al., AM disorders, cancer smooth muscle cells. J Obset Gynecol 2000 Jul; 183(1): 76- 82 and Holda et al., Cell Calcium 1996 Jul; 20(1): 43 51. Vasopressin GeneSeq WO0053755 Vasopressinis believed to have a Vasopressin activity can be determined inflammatory (Neurophysin Accession direct antidiuretic action on the using assays known in the art, for disorders II) B24085 and kidney, and it is thought to cause example, Endocr Regul 1996 Mar; immunologic B24086 vasoconstriction of the peripheral 30(I): 13-17. disorders, cancer vessels. IL-1 GeneSeq EP165654 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders P60326 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarclio (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. IL-1 mature GeneSeq EP456332 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R14855 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarclio (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. IL-1 beta GeneSeq WO9922763 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders Y08322 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarclio (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. IL-3 variants GeneSeq WO8806161 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders P80382, P80383, lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic P80384, and macrophages. Known functions Interferens: A Practical Approach, disorders, cancer P80381 include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Kitamura et al (1989) J Cell chemotaxis of neutrophils and T Physiol. 140 323-334. lymphocytes, and/or inhibition of interferons. IL-4 GeneSeq WO8702990 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders P70615 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Siegel & Mostowski (1990) J chemotaxis of neutrophils and T Immunol Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. IL-4 muteins GeneSeq WO9747744 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders W52151 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic W52152 macrophages. Known functions Interferens: A Practical Approach, disorders, cancer W52153 include stimulating proliferation of Clemens et al., eds, IRL Press, W52154 immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; W52155 cells, eosinophils, and lymphocytes), and Siegel & Mostowski (1990) J W52156 chemotaxis of neutrophils and T Immunol Methods 132, 287-295. W52157 lymphocytes, and/or inhibition of W52158 interferons. W52159 W52160 W52161 W52162 W52163 W52164 and W52165 IL-1 alpha GeneSeq EP324447 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders P90108 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarclio (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. IL-3 variants GeneSeq WO9307171 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R38561, R38562, lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic R38563, R38564, macrophages. Known functions Interferens: A Practical Approach, disorders, cancer R38565, R38566, include stimulating proliferation of Clemens et al., eds, IRL Press, R38567, R38568, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; R38569, R38570, cells, eosinophils, and lymphocytes), and Aarden et al (1987) Eur. J. R38571, and chemotaxis of neutrophils and T Immunol 17, 1411-16. R38572 lymphocytes, and/or inhibition of interferons. IL-6 GeneSeq WO9402512 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R45717 and lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic R45718 macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Aarden et al (1987) Eur. J. chemotaxis of neutrophils and T Immunol 17, 1411-16. lymphocytes, and/or inhibition of interferons. IL-13 GeneSeq WO9404680 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R48624 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Boutelier et al (1995) J. Immunol. chemotaxis of neutrophils and T Methods 181, 29. lymphocytes, and/or inhibition of interferons. IL-4 mutein GeneSeq DE4137333 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R47182 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Siegel & Mostowski (1990) J chemotaxis of neutrophils and T Immunol Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. IL-4 mutein GeneSeq DE4137333 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Y124X Accession functional cytokines synthesized by using assays known in the art: disorders R47183 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Siegel & Mostowski (1990) J chemotaxis of neutrophils and T Immunol Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. IL-4 mutein GeneSeq DE4137333 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Y124G Accession functional cytokines synthesized by using assays known in the art: disorders R47184 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Siegel & Mostowski (1990) J chemotaxis of neutrophils and T Immunol Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9317698 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Interleukin-10 Accession functional cytokines synthesized by using assays known in the art: disorders (precursor) R41664 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Thompson-Snipes et al (1991) J. chemotaxis of neutrophils and T Exp. Med. 173, 507-510. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9318783-A Interleukins are a group of multi- Interleukin activity can be determined inflammatory Interleukin-10 Accession functional cytokines synthesized by using assays known in the art: disorders R42642 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Thompson-Snipes et al (1991) J. chemotaxis of neutrophils and T Exp. Med. 173, 507-510. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP569042 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-1 Accession functional cytokines synthesized by using assays known in the art: disorders beta precursor. R42447 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarclio (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. Interleukin- GeneSeq EP578278 Interleukins are a group of multi- Interleukin activity can be determined inflammatory 1alpha Accession functional cytokines synthesized by using assays known in the art: disorders R45364 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq JP04063595 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-3 Accession functional cytokines synthesized by using assays known in the art: disorders variant R22814 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. chemotaxis of neutrophils and T 140 323-334. lymphocytes, and/or inhibition of interferons. IL-1i fragments GeneSeq EP541920 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R35484 and lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic R35485 macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarclio (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. IL-1 inhibitor GeneSeq EPS541920 Interleukins are a group of multi- Interleukin activity can be determined inflammatory (IL-li) Accession functional cytokines synthesized by using assays known in the art: disorders R35486 and lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic R35484 macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarclio (1989) chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. ICE 22 kD GeneSeq EP533350 Interleukins are a group of multi- Interleukin activity can be determined inflammatory subunit. Accession functional cytokines synthesized by using assays known in the art: disorders R33780 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. ICE 20 kD GeneSeq EP533350 Interleukins are a group of multi- Interleukin activity can be determined inflammatory subunit. Accession functional cytokines synthesized by using assays known in the art: disorders R33781 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. ICE 10 kD GeneSeq EP533350 Interleukins are a group of multi- Interleukin activity can be determined inflammatory subunit Accession functional cytokines synthesized by using assays known in the art: disorders R33782 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9317698 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Interleukin-10 Accession functional cytokines synthesized by using assays known in the art: disorders (precursor) R41664 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Thompson-Snipes et al (1991) J. chemotaxis of neutrophils and T Exp. Med. 173, 507-510. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9318783 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Interleukin-10 Accession functional cytokines synthesized by using assays known in the art: disorders R42642 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Thompson-Snipes et al (1991) J. chemotaxis of neutrophils and T Exp. Med. 173, 507-510. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP569042 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Interleukin-1 Accession functional cytokines synthesized by using assays known in the art: disorders beta precursor R42447 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. chemotaxis of neutrophils and T 140 323-334. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9403492 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-6 Accession functional cytokines synthesized by using assays known in the art: disorders R49041 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Aarden et al (1987) Eur. J. chemotaxis of neutrophils and T Immunol 17, 1411-16. lymphocytes, and/or inhibition of interferons. Mutant GeneSeq WO9411402 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Interleukin 6 Accession functional cytokines synthesized by using assays known in the art: disorders S176R R54990 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Aarden et al (1987) Eur. J. chemotaxis of neutrophils and T Immunol 17, 1411-16. lymphocytes, and/or inhibition of interferons. Interleukin 6 GeneSeq JP06145063 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R55256 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Aarden et al (1987) Eur. J. chemotaxis of neutrophils and T Immunol 17, 1411-16. lymphocytes, and/or inhibition of interferons. Interleukin 8 GeneSeq JP06100595 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-8 (IL-8) receptor Accession functional cytokines synthesized by using assays known in the art: receptor polypep- R53932 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Holmes et al (1991) Science 253, chemotaxis of neutrophils and T 1278-80. lymphocytes, and/or inhibition of interferons. Human GeneSeq U.S. Pat. No. Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-7 Accession 5,328,988 functional cytokines synthesized by using assays known in the art: disorders R59919 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Park et al (1990) J. Exp. Med. 171, chemotaxis of neutrophils and T 1073-79. lymphocytes, and/or inhibition of interferons. IL-3 containing GeneSeq WO9521254 Interleukins are a group of multi- Interleukin activity can be determined inflammatory fusion protein. Accession functional cytokines synthesized by using assays known in the art: disorders R79342 and lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic R79344 macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. chemotaxis of neutrophils and T 140 323-334. lymphocytes, and/or inhibition of interferons. IL-3 mutant GeneSeq ZA9402636 Interleukins are a group of multi- Interleukin activity can be determined inflammatory proteins Accession functional cytokines synthesized by using assays known in the art: disorders R79254, R79255, lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic R79256, R79257, macrophages. Known functions Interferens: A Practical Approach, disorders, cancer R79258, R79259, include stimulating proliferation of Clemens et al., eds, IRL Press, R79260, R79261, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; R79262, R79263, cells, eosinophils, and lymphocytes), and Giri et al (1994) EMBO J. 13 R79264, R79265, chemotaxis of neutrophils and T 2822-2830. R79266, R79267, lymphocytes, and/or inhibition of R79268, R79269, interferons. R79270, R79271, R79272, R79273, R79274, R79275, R79276, R79277, R79278, R79279, R79280, R79281, R79282, R79283, R79284, and R79285 IL-12 p40 GeneSeq AU9466072 Interleukins are a group of multi- Interleukin activity can be determined inflammatory subunit. Accession functional cytokines synthesized by using assays known in the art: disorders R63018 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. AGF GeneSeq WO9429344 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R64240 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9519786 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interlaukin-12 Accession functional cytokines synthesized by using assays known in the art: disorders 40 kD subunit R79187 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Hori et al (1987), Blood 70, 1069- chemotaxis of neutrophils and T 1078. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9530695 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-8 interleukin-15 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- receptor from R90843 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful clone P1 macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Giri et al (1994) EMBO J. 13 2822- chemotaxis of neutrophils and T 2830. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9604306 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-7 Accession functional cytokines synthesized by using assays known in the art: disorders R92796 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Park et al (1990) J. Exp. Med. 171, chemotaxis of neutrophils and T 1073-79. lymphocytes, and/or inhibition of interferons. interleukin-9 GeneSeq WO9604306 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R92797 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Yang et al (1989) Blood 74, 1880- chemotaxis of neutrophils and T 84. lymphocytes, and/or inhibition of interferons. interleukin-3 GeneSeq WO9604306 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R92801 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. chemotaxis of neutrophils and T 140 323-334. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9604306 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-5 Accession functional cytokines synthesized by using assays known in the art: disorders R92802 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. chemotaxis of neutrophils and T 140 323-334. lymphocytes, and/or inhibition of interferons. Recombinant GeneSeq DE19617202 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-16 Accession functional cytokines synthesized by using assays known in the art: disorders W33373 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Lim et al (1996) J. Immunol. 156, chemotaxis of neutrophils and T 2566-70. lymphocytes, and/or inhibition of interferons. Human IL-16 GeneSeq DE19617202 Interleukins are a group of multi- Interleukin activity can be determined inflammatory protein Accession functional cytokines synthesized by using assays known in the art: disorders W33234 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Lim et al (1996) J. Immunol. 156, chemotaxis of neutrophils and T 2566-70. lymphocytes, and/or inhibition of interferons. Thrl 17 human GeneSeq WO9708321 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin 9 Accession functional cytokines synthesized by using assays known in the art: disorders W27521 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Metl 17 human GeneSeq WO9708321 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin 9 Accession functional cytokines synthesized by using assays known in the art: disorders W27522 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Yang et al (1989) Blood 74, 1880- chemotaxis of neutrophils and T 84. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP86-4585 Interleukins are a group of multi- Interleukin activity can be determined inflammatory intracellular IL- Accession functional cytokines synthesized by using assays known in the art: disorders 1 receptor W77158 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic antagonist. macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarello (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP864585 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-18 Accession functional cytokines synthesized by using assays known in the art: disorders protein (IL-18) W77158 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and USHIO et al (1996) J. Immunol. chemotaxis of neutrophils and T 156, 4274-79. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP861663 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-18 Accession functional cytokines synthesized by using assays known in the art: disorders W77077 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and USHIO et al (1996) J. Immunol. chemotaxis of neutrophils and T 156, 4274-79. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP861663 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin Accessions functional cytokines synthesized by using assays known in the art: disorders 18 derivatives W77083, lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic W77084, macrophages. Known functions Interferens: A Practical Approach, disorders, cancer W77085, include stimulating proliferation of Clemens et al., eds, IRL Press, W77086, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; W77087, cells, eosinophils, and lymphocytes), and Ushio et al (1996) J. Immunol, 156, W77088, and chemotaxis of neutrophils and T 4274-79. W77089 lymphocytes, and/or inhibition of interferons. Interleukin-9 GeneSeq WO9827997 Interleukins are a group of multi- Interleukin activity can be determined inflammatory (IL-9) mature Accession functional cytokines synthesized by using assays known in the art: disorders protein (Thr117 W68158 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic version). macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Yang et al (1989) Blood 74, 1880- chemotaxis of neutrophils and T 84. lymphocytes, and/or inhibition of interferons. IL-9 mature GenSeq Accession WO9827997 Interleukins are a group of multi- Interleukin activity can be determined inflammatory protein variant W68157 functional cytokines synthesized by using assays known in the art: disorders (Met117 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic version) macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Yang et al (1989) Blood 74, 1880- chemotaxis of neutrophils and T 84. lymphocytes, and/or inhibition of interferons. Human IL-9 GeneSeq WO9824904 Interleukins are a group of multi- Interleukin activity can be determined inflammatory receptor protein Accession functional cytokines synthesized by using assays known in the art: disorders variant #3. W64058 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Yang et al (1989) Blood 74, 1880- chemotaxis of neutrophils and T 84. lymphocytes, and/or inhibition of interferons. Human IL-9 GenSeq Accession WO9824904 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-9 receptor protein W64060 functional cytokines synthesized by using assays known in the art: receptor polypep- variant lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful fragment macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Yang et al (1989) Blood 74, 1880- chemotaxis of neutrophils and T 84. lymphocytes, and/or inhibition of interferons. Human IL-9 GeneSeq WO9824904 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-9 receptor protein Accession functional cytokines synthesized by using assays known in the art: receptor polypep- variant #3. W64061 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Yang et al (1989) Blood 74, 1880- chemotaxis of neutrophils and T 84. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9817689 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Interleukin-12 Accession functional cytokines synthesized by using assays known in the art: disorders p40 protein W51311 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Hori et al (1987), Blood 70, 1069- chemotaxis of neutrophils and T 1078. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9817689 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Interleukin-12 Accession functional cytokines synthesized by using assays known in the art: disorders p35 protein W51312 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Hori et al (1987), Blood 70, 1069- chemotaxis of neutrophils and T 1078. lymphocytes, and/or inhibition of interferons. Human protein GeneSeq DE19649233- Interleukins are a group of multi- Interleukin activity can be determined inflammatory with IL-16 Accession functional cytokines synthesized by using assays known in the art: disorders activity W63753 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Lim et al (1996) J. Immunol. 156, chemotaxis of neutrophils and T 2566-70. lymphocytes, and/or inhibition of interferons. Human protein GeneSeq DE19649233- Interleukins are a group of multi- Interleukin activity can be determined inflammatory with IL-16 Accession functional cytokines synthesized by using assays known in the art: disorders activity W59425 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Lim et al (1996) J. Immunol. 156, chemotaxis of neutrophils and T 2566-70. lymphocytes, and/or inhibition of interferons. Human GeneSeq U.S. Pat. No. Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-15 Accession 5,747,024 functional cytokines synthesized by using assays known in the art: disorders W53878 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Giri et al (1994) EMBO J. 13 2822- chemotaxis of neutrophils and T 2830. lymphocytes, and/or inhibition of interferons. Human wild- GeneSeq WO9747744 Interleukins are a group of multi- Interleukin activity can be determined inflammatory type Accession functional cytokines synthesized by using assays known in the art: disorders interleukin-4 W52149 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic (hIL-4) protein macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Siegel & Mostowski (1990) J chemotaxis of neutrophils and T Immunol Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. interleukin-4 GeneSeq WO9747744 Interleukins are a group of multi- Interleukin activity can be determined inflammatory muteins Accessions functional cytokines synthesized by using assays known in the art: disorders W52150, W52151, lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic W52153, W52154, macrophages. Known functions Interferens: A Practical Approach, disorders, cancer W52155, W52156, include stimulating proliferation of Clemens et al., eds, IRL Press, W52157, W52158, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; W52159, W52160, cells, eosinophils, and lymphocytes), and Siegel & Mostowski (1990) J W52161, W52162, chemotaxis of neutrophils and T Immunol Methods 132, 287-295. W52163, W52164, lymphocytes, and/or inhibition of W52165, interferons. W52166, and W52167 Human GeneSeq WO9935268 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin 1 Accession functional cytokines synthesized by using assays known in the art: disorders delta Y28408 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarello (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9935268 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-1 Accession functional cytokines synthesized by using assays known in the art: disorders receptor Y24395 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic antagonist beta macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarello (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. Human EDIRF GeneSeq WO9932632 Interleukins are a group of multi- Interleukin activity can be determined inflammatory II protein Accession functional cytokines synthesized by using assays known in the art: disorders sequence Y22199 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human EDIRF GeneSeq WO9932632 Interleukins are a group of multi- Interleukin activity can be determined inflammatory I protein Accession functional cytokines synthesized by using assays known in the art: disorders sequence Y22197 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL- GeneSeq WO9919480 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-1RD10 1RD10 protein Accession functional cytokines synthesized by using assays known in the art: receptor polypep- sequence Y14131 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin activites. immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarello (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. Human IL- GeneSeq WO9919480 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-1RD10 1RD9 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- Y14122 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin activites. immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarello (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. Human DNAX GeneSeq WO9919491 Interleukins are a group of multi- Interleukin activity can be determined inflammatory interleukin-40 Accession functional cytokines synthesized by using assays known in the art: disorders Y09196 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. (DIL-40) GeneSeq WO9919491 Interleukins are a group of multi- Interleukin activity can be determined inflammatory alternative Accession functional cytokines synthesized by using assays known in the art: disorders sequence Y09197 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-11 GeneSeq WO9405318 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R50176 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Lu et al (1994) J immunol. chemotaxis of neutrophils and T Methods 173, 19. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP566410 Interleukins are a group of multi- Interleukin activity can be determined inflammatory adipogenesis Accession functional cytokines synthesized by using assays known in the art: disorders inhibitory factor R43260 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-11 GeneSeq JP08127539 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders W02202 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Lu et al (1994) J immunol. chemotaxis of neutrophils and T Methods 173, 19. lymphocytes, and/or inhibition of interferons. IL-14 GeneSeq WO9416074 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R55800 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Ambrus et al (1993) PNAS 90, chemotaxis of neutrophils and T 63330-34. lymphocytes, and/or inhibition of interferons. IL-17 receptor GeneSeq U.S. Pat. No. Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-17 Accession 6,072,033 functional cytokines synthesized by using assays known in the art: receptor polypep- B03807 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin activites. immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Yao et al (1995) J. Immunol. 155, chemotaxis of neutrophils and T 5483-86. lymphocytes, and/or inhibition of interferons. IL-17 GeneSeq WO9518826 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders R76573 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Yao et al (1995) J. Immunol. 155, chemotaxis of neutrophils and T 5483-86. lymphocytes, and/or inhibition of interferons. CTLA-8 GeneSeq WO9704097 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders W13651 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-19 GeneSeq WO9808870 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders W37935 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Gallagher et al (2000) Genes chemotaxis of neutrophils and T Immun. 1, 442-50. lymphocytes, and/or inhibition of interferons. IL-21 (TIF) GeneSeq WO0024758 Interleukins are a group of multi- Interleukin activity can be determined inflammatory Accession functional cytokines synthesized by using assays known in the art: disorders Y92879 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Parrish-Novak et al (2000) Nature chemotaxis of neutrophils and T 408, 57-63. lymphocytes, and/or inhibition of interferons. IL-8 receptor GeneSeq WO9306229 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-8 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- R33420 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Holmes et al (1991) Science 253, chemotaxis of neutrophils and T 1278-80.. lymphocytes, and/or inhibition of interferons. Human type II GeneSeq U.S. Pat. No. Interleukins are a group of multi- Interleukin activity can be determined Soluble type II interleukin-1 Accession 5,464,937 functional cytokines synthesized by using assays known in the art: interleukin-1 receptor R85480 lymphocytes, monocytes, and Matthews et al., in Lymphokines and receptor polypep- macrophages. Known functions Interferens: A Practical Approach, tides may be useful include stimulating proliferation of Clemens et al., eds, IRL Press, for inhibiting immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; interleukin cells, eosinophils, and lymphocytes), and Orencole & Dinarello (1989) activities. chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP638644 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-12 interleukin-12 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- receptor R69632 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Hori et al (1987), Blood 70, 1069- chemotaxis of neutrophils and T 1078. lymphocytes, and/or inhibition of interferons. Interleukin 8 GeneSeq U.S. Pat. No. Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-8 receptor B Accession 5,440,021 functional cytokines synthesized by using assays known in the art: receptor B polypep- R80758 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Holmes et al (1991) Science 253, chemotaxis of neutrophils and T 1278-80. lymphocytes, and/or inhibition of interferons. Human IL-8 GeneSeq JP08103276 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-8 receptor protein Accession B09989 functional cytokines synthesized by using assays known in the art: receptor A polypep- hIL8RA lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Holmes et al (1991) Science 253, chemotaxis of neutrophils and T 1278-80. lymphocytes, and/or inhibition of interferons. Human IL-8 GeneSeq JP08103276 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-8 receptor protein Accession B09990 functional cytokines synthesized by using assays known in the art: receptor polypep- hIL8R lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Holmes et al (1991) Science 253, chemotaxis of neutrophils and T 1278-80. lymphocytes, and/or inhibition of interferons. Interleukin-2 GeneSeq WO9621732- Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-2 receptor Accession functional cytokines synthesized by using assays known in the art: receptor polypep- associated R97569 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful protein p43 macrophages. Known functions Interferons: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Gillis et al (1978) J. Immunol. 120, chemotaxis of neutrophils and T 2027. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9629408 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-17 interleukin-17 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- receptor W04185 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Yao et al (1995) J. Immunol. 155, chemotaxis of neutrophils and T 5483-86. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9619574 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-11 interleukin-11 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- receptor R99090 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Lu et al (1994) J immunol. chemotaxis of neutrophils and T Methods 173, 19. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9623067 Interleukins are a group of multi- Interleukin activity can be determined Inflammatory interleukin-1 Accession functional cytokines synthesized by using assays known in the art: disorders receptor W01911 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic accessory macrophages. Known functions Interferens: A Practical Approach, disorders, cancer protein include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; cells, eosinophils, and lymphocytes), and Orencole & Dinarello (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. AGF Protein GeneSeq U.S. Pat. No. Interleukins are a group of multi- Interleukin activity can be determined Inflammatory Accession 5,488,032 functional cytokines synthesized by using assays known in the art: disorders R92749 lymphocytes, monocytes, and Matthews et al., in Lymphokines and immunologic macrophages. Known functions Interferens: A Practical Approach, disorders, cancer include stimulating proliferation of Clemens et al., eds, IRL Press, immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human GeneSeq W09607739 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-type-3 interleukin-1 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- type-3 receptor R91064 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities cells, eosinophils, and lymphocytes), and Orencole & Dinarello (1989) chemotaxis of neutrophils and T Cytokine 1, 14-20. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9720926 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-13 beta interleukin-13 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- beta receptor W24972 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Boutelier et al (1995) J. Immunol. chemotaxis of neutrophils and T Methods 181, 29. lymphocytes, and/or inhibition of interferons. Human GeneSeq WO9720926 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-13 alpha interleukin-13 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- alpha receptor W24973 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Boutelier et al (1995) J. Immunol. chemotaxis of neutrophils and T Methods 181, 29. lymphocytes, and/or inhibition of interferons. Human GeneSeq U.S. Pat. No. Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-4 interleukin-4 Accession 5,599,905 functional cytokines synthesized by using assays known in the art: receptor polypep- receptor W13499 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Siegel & Mostowski (1990) J chemotaxis of neutrophils and T Immunol Methods 132, 287-295. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP759466 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-12 beta-2 interleukin-12 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- beta-2 receptor W12771 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Hori et al (1987), Blood 70, 1069- chemotaxis of neutrophils and T 1078. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP759466 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-12 beta-1 interleukin-12 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- beta-1 receptor. W12772 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Hori et al (1987), Blood 70, 1069- chemotaxis of neutrophils and T 1078. lymphocytes, and/or inhibition of interferons. Human IL-9 GeneSeq WO9824904 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-9 receptor protein Accessions functional cytokines synthesized by using assays known in the art: receptor polypep- W64055, W64056, lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful and W64057 macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Yang et al (1989) Blood 74, 1880- chemotaxis of neutrophils and T 84. lymphocytes, and/or inhibition of interferons. IL-10 receptor GeneSeq U.S. Pat. No. Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-10 Accession 5,716,804 functional cytokines synthesized by using assays known in the art: receptor polypep- W41804 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Thompson-Snipes et al (1991) J. chemotaxis of neutrophils and T Exp. Med. 173, 507-510. lymphocytes, and/or inhibition of interferons. Human IL-6 GeneSeq JP11196867 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-6 receptor Accession Y30938 functional cytokines synthesized by using assays known in the art: receptor polypep- lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Aarden et al (1987) Eur. J. chemotaxis of neutrophils and T Immunol 17, 1411-16. lymphocytes, and/or inhibition of interferons. Il-17 receptor GeneSeq U.S. Pat. No. Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-17 Accession Y97181 6,096,305 functional cytokines synthesized by using assays known in the art: receptor polypep- lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Yao et al (1995) J. Immunol. 155, chemotaxis of neutrophils and T 5483-86. lymphocytes, and/or inhibition of interferons. Il-17 receptor GeneSeq U.S. Pat. No. Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-17 Accession Y97131 6,100,235 functional cytokines synthesized by using assays known in the art: receptor polypep- lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Yao et al (1995) J. Immunol. 155, chemotaxis of neutrophils and T 5483-86. lymphocytes, and/or inhibition of interferons. Human GeneSeq EP509826 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-3 interleukin-3 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- receptor R25300 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. chemotaxis of neutrophils and T 140 323-334. lymphocytes, and/or inhibition of interferons. Human GM- GeneSeq WO9102063 Interleukins are a group of multi- Interleukin activity can be determined Soluble GM-CSF CSF receptor Accession functional cytokines synthesized by using assays known in the art: receptor polypep- R10919 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. activities. cells, eosinophils, and lymphocytes), chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. Human IL-5 GeneSeq EP492214 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-5 receptor alpha Accession functional cytokines synthesized by using assays known in the art: receptor alpha chain R25064 lymphocytes, monocytes, and Matthews et al., in Lymphokines and polypeptides may be macrophages. Known functions Interferens: A Practical Approach, useful for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. chemotaxis of neutrophils and T 140 323-334. lymphocytes, and/or inhibition of interferons. Il-5 receptor GeneSeq WO9847923 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-5 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- W82842 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), Kitamura et al (1989) J Cell Physiol. chemotaxis of neutrophils and T 140 323-334. lymphocytes, and/or inhibition of interferons. Il-6 receptor GeneSeq JP05091892 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-6 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- R37215 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Aarden et al (1987) Eur. J. chemotaxis of neutrophils and T Immunol 17, 1411-16. lymphocytes, and/or inhibition of interferons. Human B cell GeneSeq AU8928720 Interleukins are a group of multi- Interleukin activity can be determined Soluble B cell stimulating Accession P90525 functional cytokines synthesized by using assays known in the art: stimulating factor-2 factor-2 lymphocytes, monocytes, and Matthews et al., in Lymphokines and receptor polypep- receptor macrophages. Known functions Interferens: A Practical Approach, tides may be useful include stimulating proliferation of Clemens et al., eds, IRL Press, for inhibiting immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225. interleukin cells, eosinophils, and lymphocytes), activities. chemotaxis of neutrophils and T lymphocytes, and/or inhibition of interferons. IL-7 receptor GeneSeq EP403114 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-7 clone Accession functional cytokines synthesized by using assays known in the art: receptor polypep- R08330 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Park et al (1990) J. Exp. Med. 171, chemotaxis of neutrophils and T 1073-79. lymphocytes, and/or inhibition of interferons. EPO receptor; GeneSeq WO9008822 EPO Receptor is involved in the EPO Receptor activity can be Inflammatory EPOR Accession proliferation and differentiation of determined using assays known in the disorders, R06512 erythroblasts. art, such as, J Biol Chem 2001 Mar 23; immunologic 276(12: 8995-9002; JAK2 protein disorders, cancer, tyrosine kinase activity: Blood 1994 erythroblast Sep 1; 84(5): 1501-7 and Mol Cell Biol. proliferation and 1994 Oct; 14(10: 6506-14. differentiation IL-15 receptor GeneSeq WO9530695 Interleukins are a group of multi- Interleukin activity can be determined Soluble IL-15 Accession functional cytokines synthesized by using assays known in the art: receptor polypep- R90843 lymphocytes, monocytes, and Matthews et al., in Lymphokines and tides may be useful macrophages. Known functions Interferens: A Practical Approach, for inhibiting include stimulating proliferation of Clemens et al., eds, IRL Press, interleukin immune cells (e.g., T helper cells, B Washington, D.C. 1987, pp. 221-225; activities. cells, eosinophils, and lymphocytes), and Giri et al (1994) EMBO J. 13 2822- chemotaxis of neutrophils and T 2830. lymphocytes, and/or inhibition of interferons. CD137; 4-1BB GeneSeq WO9507984 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble 4-1BB Receptor Accession NF-kB activation, and co- and B and T cell co-stimulation can be receptor polypep- Protein R70977 stimulation of immune cells such as determined using assays known in the tides may be useful T and B cells. art: Moore et al., 1999, Science, for inhibiting 285(5425): 260-3; Song HY et al., 1997 apoptosis, NF-kB Proc Natl Acad Sci USA 94(18): 9792- activation, and/or 6; Epsevik and Nissen-Meyer, 1986, J. co-stimulation of Immunol. Methods. immune cells such as B and T cells. BCMA GeneSeq WO0068378 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble BCMA Accession Y71979 NF-kB activation, and co- and B and T cell co-stimulation can be receptor polypep- stimulation of immune cells such as determined using assays known in the tides may be useful T and B cells. art: Moore et al., 1999, Science, for inhibiting 285(5425): 260-3; Song HY et al., 1997 apoptosis, NF-kB Proc Natl Acad Sci USA 94(18): 9792- activation, and/or 6; Epsevik and Nissen-Meyer, 1986, J. co-stimulation of Immunol. Methods. immune cells such as B and T cells. CD27 GeneSeq WO9201049 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble CD27 Accession NF-kB activation, and co- and B and T cell co-stimulation can be polypeptides may be R20814 stimulation of immune cells such as determined using assays known in the useful for inhibiting T and B cells. art: Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or Proc Natl Acad Sci USA 94(18): 9792- co-stimulation of 6; Epsevik and Nissen-Meyer, 1986, J. immune cells such Immunol. Methods. as B and T cells. CD30 GeneSeq DE4200043 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble CD30 Accession NF-kB activation, and co- and B and T cell co-stimulation can be polypeptides may be R35478 stimulation of immune cells such as determined using assays known in the useful for inhibiting T and B cells. art: Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or Proc Natl Acad Sci USA 94(18): 9792- co-stimulation of 6; Epsevik and Nissen-Meyer, 1986, J. immune cells such Immunol. Methods. as B and T cells. CD40 GeneSeq WO9945944 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble CD40 Accession NF-kB activation, and co- and B and T cell co-stimulation can be polypeptides may be Y33499 stimulation of immune cells such as determined using assays known in the useful for inhibiting T and B cells. art: Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or Proc Natl Acad Sci USA 94(18): 9792- co-stimulation of 6; Epsevik and Nissen-Meyer, 1986, J. immune cells such Immunol. Methods. as B and T cells. EDAR Genbank Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Immune Disorders, Accession NF-kB activation, and co- and B and T cell co-stimulation can be Lymphomas, X- AAD50077 stimulation of immune cells such as determined using assays known in the linked hypohidrotic T and B cells. art: Moore et al., 1999, Science, ectodermal dysplasia 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. OX40; ACT-4 GeneSeq WO9512673 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Immune Disorders, Accession R74737 NF-kB activation, and co- and B and T cell co-stimulation can be Lymphomas, T cell stimulation of immune cells such as determined using assays known in the disorders T and B cells. art: Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. TACI GeneSeq WO9839361 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble TACI Accession NF-kB activation, and co- and B and T cell co-stimulation can be receptor polypep- W75783 stimulation of immune cells such as determined using assays known in the tides may be useful T and B cells. art: Moore et al., 1999, Science, for inhibiting 285(5425): 260-3; Song HY et al., 1997 apoptosis, NF-kB Proc Natl Acad Sci USA 94(18): 9792- activation, and/or 6; Epsevik and Nissen-Meyer, 1986, J. co-stimulation of Immunol. Methods. immune cells such as B and T cells. TNF-R GeneSeq AU9058976 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble TNF-R Accession R10986 NF-kB activation, and co- and B and T cell co-stimulation can be receptor polypep- stimulation of immune cells such as determined using assays known in the tides may be useful T and B cells. art: Moore et al., 1999, Science, for inhibiting 285(5425): 260-3; Song HY et al., 1997 apoptosis, NF-kB Proc Natl Acad Sci USA 94(18): 9792- activation, and/or 6; Epsevik and Nissen-Meyer, 1986, J. co-stimulation of Immunol. Methods. immune cells such as B and T cells. TNF-RII; TNF GeneSeq EP418014 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble TNFR-II p75 receptor; Accession R11141 NF-kB activation, and co- and B and T cell co-stimulation can be receptor polypep- Death Receptor stimulation of immune cells such as determined using assays known in the tides may be useful T and B cells. art: Moore et al., 1999, Science, for inhibiting 285(5425): 260-3; Song HY et al., 1997 apoptosis, NF-kB Proc Natl Acad Sci USA 94(18): 9792- activation, and/or 6; Epsevik and Nissen-Meyer, 1986, J. co-stimulation of Immunol. Methods. immune cells such as B and T cells. hAPO-4; TROY GeneSeq WO9911791 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Immune Disorders, Accession NF-kB activation, and co- and B and T cell co-stimulation can be Cancers W93581 stimulation of immune cells such as determined using assays known in the T and B cells. art: Moore et al., 1999, Science, 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. TNF-alpha GeneSeq EP205038 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory precursor Accession P60074 NF-kB activation, and co- and B and T cell co-stimulation can be disorders stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. Human TNF- GeneSeq EP619372 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory alpha Accession R62463 NF-kB activation, and co- and B and T cell co-stimulation can be disorders stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. Human TNF- GeneSeq EP563714 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory alpha Accession R42679 NF-kB activation, and co- and B and T cell co-stimulation can be disorders stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. Human TNF- GeneSeq WO0064479 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory beta (LT-alpha) Accession B37799 NF-kB activation, and co- and B and T cell co-stimulation can be disorders stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. LT-alpha GeneSeq EP250000 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory Accession P70107 NF-kB activation, and co- and B and T cell co-stimulation can be disorders stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. LT-beta GeneSeq WO9413808 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory Accession R56869 NF-kB activation, and co- and B and T cell co-stimulation can be disorders stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. OPGL GeneSeq WO9846751 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory Accession NF-kB activation, and co- and B and T cell co-stimulation can be disorders W83195 stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer, 285(5425): 260-3; Song HY et al., 1997 loss of bone mass Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. FasL GeneSeq WO9903999 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory Accession NF-kB activation, and co- and B and T cell co-stimulation can be disorders W98071 stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. FasL GeneSeq WO9903998 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory Accession NF-kB activation, and co- and B and T cell co-stimulation can be disorders W95041 stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. CD27L GeneSeq WO9405691 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory Accession R50121 NF-kB activation, and co- and B and T cell co-stimulation can be disorders stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. CD30 ligand GeneSeq WO9324135 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory Accession R45007 NF-kB activation, and co- and B and T cell co-stimulation can be disorders stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. CD40L GeneSeq WO9529935 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory Accession R85486 NF-kB activation, and co- and B and T cell co-stimulation can be disorders stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. 4-1BB ligand GeneSeq U.S. Pat. No. Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory Accession 5,674,704 NF-kB activation, and co- and B and T cell co-stimulation can be disorders W26657 stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. FAS Ligand GeneSeq WO0058465 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Soluble DcR3 Inhibitory Accession B19335 NF-kB activation, and co- and B and T cell co-stimulation can be polypeptides may be Protein (DcR3) stimulation of immune cells such as determined using assays known in the useful for inhibiting T and B cells. art: Moore et al., 1999, Science, apoptosis, NF-kB 285(5425): 260-3; Song HY et al., 1997 activation, and/or Proc Natl Acad Sci USA 94(18): 9792- co-stimulation of 6; Epsevik and Nissen-Meyer, 1986, J. immune cells such Immunol. Methods. as B and T cells. OX40L GeneSeq WO9521915 Activities associated with apoptosis, Apoptosis activity, NF-kB activation, Inflammatory Accession R79903 NF-kB activation, and co- and B and T cell co-stimulation can be disorders stimulation of immune cells such as determined using assays known in the immunologic T and B cells. art: Moore et al., 1999, Science, disorders, cancer 285(5425): 260-3; Song HY et al., 1997 Proc Natl Acad Sci USA 94(18): 9792- 6; Epsevik and Nissen-Meyer, 1986, J. Immunol. Methods. Protease GeneSeq WO9106561 Peptides that inhibit the HIV protease activities are known in HIV, inflammatory inhibitor Accessions function/binding of HIV the art: HIV protease assays: disorders, immuno- peptides R12435, R12436, EP0387231. One can modify the assay logic disorders, R12437, R12438, to look for inhibition using any of the cancer, viral R12439, R12440, disclosed protease inhibitor infections and R1244 polypeptides. Retroviral GeneSeq EP387231 Peptides that inhibit the HIV protease activities are known in HIV, inflammatory protease Accessions function/binding of HIV the art: HIV protease assays: disorders, immuno- inhibitors R06660, R06661, EP0387231. One can modify the assay logic disorders, R06662, R06663, to look for inhibition using any of the cancer, viral R06664, R06665, disclosed protease inhibitor infections R06666, R06667, polypeptides. R06668, R06669, R06670, R06671, R06672, R06673, R06674, R06675, and R06676 HIV protease GeneSeq WO9301828 Peptides that inhibit the HIV protease activities are known in HIV, inflammatory inhibiting Accessions function/binding of HIV the art: HIV protease assays: disorders, immuno- peptides R59293, R59294, EP0387231. One can modify the assay logic disorders, R59295, R59296, to look for inhibition using any of the cancer, viral R59297, disclosed protease inhibitor infections R59298, R59299, polypeptides. R592300, R59301, R59302, R59301, R59302, R59303, R59304, R59305, R59306, R59307, R59308, R59309, R59310, R59311, R59312, R59313, R59314, R59315, R59316, R59317 R59318, R59319, R59320, R59321, R59322, R59323, R59324, R59325, R59326, R59327, R59328, R59329, R59330, R59331, R59332, R59333, R59334, R59335, R59336, R59337, R59338, R59339, R59340, R59341, R59342, R59343, R59344, R59345, R59346, R59347, R59348, R59349, and R59350 HIV-1 protease GeneSeq DE4412174 Peptides that inhibit the HIV protease activities are known in HIV, inflammatory inhibitors Accessions function/binding of HIV the art: HIV protease assays: disorders, immuno- R86326, R86327, EP0387231. One can modify the assay logic disorders, R86328, R86329, to look for inhibition using any of the cancer, viral R86330, R86331, disclosed protease inhibitor infections R86332, R86333, polypeptides. R86334, R86335, R86336, R86337, R86338, R86339, R86340, R86341, R86342, R86343, R86344, R86345, R86346, R86347, R86348, R86349, R86350, R86351, R86352, R86353, R86354, R86355, R86356, R86357, R86358, R86359, R86360, R86361, R86362, R86363, R86364, R86365, R86366, R86367, R86368, R86369, R86370, and R86371 HIV Inhibitor GeneSeq WO9959615 Peptides that inhibit the HIV protease activities are known in HIV, inflammatory Peptide Accession function/binding of HIV the art: HIV protease assays: disorders, immuno- Y89687 EP0387231. One can modify the assay logic disorders, to look for inhibition using any of the cancer, viral disclosed protease inhibitor infections polypeptides. HIV Inhibitor GenSeq WO9948513 Peptides that inhibit the HIV protease activities are known in HIV, inflammatory Peptide Accession Y31955 function/binding of HIV the art: HIV protease assays: disorders, immuno- EP0387231. One can modify the assay logic disorders, to look for inhibition using any of the cancer, viral disclosed protease inhibitor infections polypeptides. HIV Inhibitor Science 291, 884 Peptides that inhibit the HIV protease activities are known in HIV, inflammatory Peptide (2001); Published function/binding of HIV the art: HIV protease assays: disorders, immuno- online 12 Jan. EP0387231. One can modify the assay logic disorders, 2001; to look for inhibition using any of the cancer, viral 10.1126/science.1 disclosed protease inhibitor infections 057453 polypeptides. Human GeneSeq WO9509232 Chemokines are a family of related Chemokine activities can be determined Immune disorders, monocyte Accession small, secreted proteins involved in using assays known in the art: Methods particularly useful chemoattractant R73915 biological processes ranging from in Molecular Biology, 2000, vol. 138: for treating bacterial factor hMCP-3 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. and/or viral leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. menigitis this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9509232 Chemokines are a family of related Chemokine activities can be determined Immune disorders, monocyte Accession small, secreted proteins involved in using assays known in the art: Methods particularly useful chemoattractant R73914 biological processes ranging from in Molecular Biology, 2000, vol. 138: for treating bacterial factor hMCP-1 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. and/or viral leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. menigitis this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human gro-beta GeneSeq WO9429341 Chemokines are a family of related Chemokine activities can be determined Immune disorders, chemokine Accessions small, secreted proteins involved in using assays known in the art: Methods inflammatory dis- R66699 and biological processes ranging from in Molecular Biology, 2000, vol. 138: orders, blood-related W17671 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, stem cell leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. transplantation, this family are involved in a similar- Power. cancer ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human gro- GeneSeq WO9429341 Chemokines are a family of related Chemokine activities can be determined Immune disorders, Accessions small, secreted proteins involved in using assays known in the art: Methods inflammatory dis- gamma R66700 and biological processes ranging from in Molecular Biology, 2000, vol. 138: orders, blood-related chemokine W17672 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, stem cell leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. transplantation, this family are involved in a similar- Power. cancer ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human gro- GeneSeq WO9429341 Chemokines are a family of related Chemokine activities can be determined Immune disorders, alpha Accessions small, secreted proteins involved in using assays known in the art: Methods inflammatory dis- chemokine R66698 and biological processes ranging from in Molecular Biology, 2000, vol. 138: orders, blood-related W18024 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, stem cell leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. transplantation, this family are involved in a similar- Power. cancer ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9632481 Chemokines are a family of related Chemokine activities can be determined Immune disorders, eosinophil- Accession small, secreted proteins involved in using assays known in the art: Methods particularly treat- expressed W05186 biological processes ranging from in Molecular Biology, 2000, vol. 138: ment of eosino- chemokine hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. philia, inflammation, (EEC) leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. allergies, asthma, this family are involved in a similar- Power. leukaemia and ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. lymphoma cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related Chemokine activities can be determined Cancer and blood- protein PF4-414 Accessions small, secreted proteins involved in using assays known in the art: Methods related disorders, Full-Length and R92318 and biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly Mature R99809 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. myelosuppression leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related Chemokine activities can be determined Cancer and blood- protein IL-8M3 Accession small, secreted proteins involved in using assays known in the art: Methods related disorders, R99812 biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. myelosuppression leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ; cluding inflammation, allergy, tissue and Holmes et al (1991) Science 253, rejection, viral infection, and tumor 1278-80. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9613587 Chemokines are a family of related Chemokine activities can be determined Cancer and blood- interleukin-8 Accession small, secreted proteins involved in using assays known in the art: Methods related disorders, (IL-8) R99814 biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. myelosuppression leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ; cluding inflammation, allergy, tissue and Holmes et al (1991) Science 253, rejection, viral infection, and tumor 1278-80. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related Chemokine activities can be determined Cancer and blood- protein IL-8M1 Accessions small, secreted proteins involved in using assays known in the art: Methods related disorders, Full-Length and R99815 and biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly Mature R99803 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. myelosuppression leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ; cluding inflammation, allergy, tissue and Holmes et al (1991) Science 253, rejection, viral infection, and tumor 1278-80. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related Chemokine activities can be determined Cancer and blood- protein IL-8M8 Accessions small, secreted proteins involved in using assays known in the art: Methods related disorders, Full-Length and R99816 and biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly Mature R99805 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. myelosuppression leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ; cluding inflammation, allergy, tissue and Holmes et al (1991) Science 253, rejection, viral infection, and tumor 1278-80. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related Chemokine activities can be determined Cancer and blood- protein IL-8M8 Accessions small, secreted proteins involved in using assays known in the art: Methods related disorders, Full-Length and R99817 and biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly Mature R99806 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. myelosuppression. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ; cluding inflammation, allergy, tissue and Holmes et al (1991) Science 253, rejection, viral infection, and tumor 1278-80. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related Chemokine activities can be determined Cancer and blood- protein IL-8M8 Accessions small, secreted proteins involved in using assays known in the art: Methods related disorders, Full-Length and R99818 and biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly Mature R99804 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. myelosuppression. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ; cluding inflammation, allergy, tissue and Holmes et al (1991) Science 253, rejection, viral infection, and tumor 1278-80. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related Chemokine activities can be determined Cancer and blood- protein IL-8M8 Accessions small, secreted proteins involved in using assays known in the art: Methods related disorders, Full-Length and R99819 and biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly Mature R99807 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. myelosuppression. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine-like GeneSeq WO9613587 Chemokines are a family of related Chemokine activities can be determined Cancer and blood- protein IL-8M8 Accessions small, secreted proteins involved in using assays known in the art: Methods related disorders, Full-Length and R99822 and biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly Mature R9807 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. myelosuppression. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human foetal GeneSeq WO9622374 Chemokines are a family of related Chemokine activities can be determined Immune disorders spleen ex- Accession R98499 small, secreted proteins involved in using assays known in the art: Methods pressed chemo- biological processes ranging from in Molecular Biology, 2000, vol. 138: kine, FSEC hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Liver expressed GeneSeq WO9616979 Chemokines are a family of related Chemokine activities can be determined Inflammation of the chemokine- Accession R95689 small, secreted proteins involved in using assays known in the art: Methods liver 1(LVEC-1) biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Liver expressed GeneSeq WO9616979 Chemokines are a family of related Chemokine activities can be determined Inflammation of the chemokine- Accession R95690 small, secreted proteins involved in using assays known in the art: Methods liver 2(LVEC-2) biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Pituitary GeneSeq WO9616979 Chemokines are a family of related Chemokine activities can be determined Inflammation, expressed Accession R95691 small, secreted proteins involved in using assays known in the art: Methods particularly of the chemokine biological processes ranging from in Molecular Biology, 2000, vol. 138: liver (PGEC) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Adenoid- GeneSeq WO9617868 Chemokines are a family of related Chemokine activities can be determined Inflammation, expressed Accession R97664 small, secreted proteins involved in using assays known in the art: Methods angiogenesis, chemokine biological processes ranging from in Molecular Biology, 2000, vol. 138: tumorigenesis, (ADEC) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. musculoskeletal leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9741230 Chemokines are a family of related Chemokine activities can be determined Immune disorders, chemokineCC-2 Accession small, secreted proteins involved in using assays known in the art: Methods cell migration, W38170 biological processes ranging from in Molecular Biology, 2000, vol. 138: proliferation, and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. differentiation leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9741230 Chemokines are a family of related Chemokine activities can be determined Immune disorders, chemokine Accession small, secreted proteins involved in using assays known in the art: Methods cell migration, HCC-1 W38171 biological processes ranging from in Molecular Biology, 2000, vol. 138: proliferation, and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. differentiation leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9741230 Chemokines are a family of related Chemokine activities can be determined Immune disorders, chemokine CC- Accession small, secreted proteins involved in using assays known in the art: Methods cell migration, 3 W38172 biological processes ranging from in Molecular Biology, 2000, vol. 138: proliferation, and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. differentiation leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Novel GeneSeq WO9739126 Chemokines are a family of related Chemokine activities can be determined Immune disorders, betachemokine Accession small, secreted proteins involved in using assays known in the art: Methods vascular disorders, designated W27271 biological processes ranging from in Molecular Biology, 2000, vol. 138: cancer PTEC hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CX3C GeneSeq WO9727299 Chemokines are a family of related Chemokine activities can be determined Immune disorders, 111 amino acid Accession small, secreted proteins involved in using assays known in the art: Methods inflammatory chemokine W23344 biological processes ranging from in Molecular Biology, 2000, vol. 138: diseases, abnormal hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. proliferation, leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. regeneration, this family are involved in a similar- Power. degeneration, and ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. atrophy cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CCF18 GeneSeq WO9721812 Chemokines are a family of related Chemokine activities can be determined Abnormal chemokine Accession small, secreted proteins involved in using assays known in the art: Methods physiology and W25942 biological processes ranging from in Molecular Biology, 2000, vol. 138: development hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, can also leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. be used as an anti- this family are involved in a similar- Power. viral agent ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human beta- GeneSeq WO9725427 Chemokines are a family of related Chemokine activities can be determined Chemotaxis, blood- chemokine Accession small, secreted proteins involved in using assays known in the art: Methods related disorders, H1305 (MCP-2) W26655 biological processes ranging from in Molecular Biology, 2000, vol. 138: viral infection, HIV, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. wound healing, leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. cancer this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9712914 Chemokines are a family of related Chemokine activities can be determined Inflammatory and eosinocyte CC Accession small, secreted proteins involved in using assays known in the art: Methods immune disorders type chemokine W14990 biological processes ranging from in Molecular Biology, 2000, vol. 138: eotaxin hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human thymus GeneSeq WO9711969 Chemokines are a family of related Chemokine activities can be determined Inflammatory and and activation Accession small, secreted proteins involved in using assays known in the art: Methods immune disorders regulated W14018 biological processes ranging from in molecular Biology, 2000, vol. 138: cytokine hematopoiesis, angiogenesis, and Chemokine Protocols, Edited by A. E. (TARC) leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9712041 Chemokines are a family of related Chemokine activities can be determined Cancer, would chemokine Accession small, secreted proteins involved in using assays known in the art: Methods healing, immune beta-8 short W16315 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders forms hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Microphage GeneSeq WO9640923 Chemokines are a family of related Chemokine activities can be determined Inflammatory derived Accession small, secreted proteins involved in using assays known in the art: Methods diseases, wound chemokine, W20058 biological processes ranging from in Molecular Biology, 2000, vol. 138: healin, angiogenesis MDC hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9844117 Chemokines are a family of related Chemokine activities can be determined Inflammatory and chemokine Accession small, secreted proteins involved in using assays known in the art: Methods immune diseases ZSIG-35 W30565 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Primate CC GeneSeq WO98328658 Chemokines are a family of related Chemokine activities can be determined Immune and chemokine Accesssion small, secreted proteins involved in using assays known in the art: Methods inflammatory “ILINCK” W69990 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, abnormal hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. proliferation, regen- leukocyte trafficking. I. Proudfoot, T. N. C. Wells, and C. A. eration, generation Power. and atrophy © Humana Press Inc., Totowa, NJ. disorders Primate CXC GeneSeq WO9832858 Chemokines are a family of related Chemokine activities can be determined Immune and chemokine Accession small, secreted proteins involved in using assays known in the art: Methods inflammatory “IBICK” W69989 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, abnormal hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. proliferation, regen- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. eration, generation this family are involved in a similar- Power. and atrophy ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CC-type GeneSeq WO9831809 Chemokines are a family of related Chemokine activities can be determined Immune, chemokine Accession small, secreted proteins involved in using assays known in the art: Methods inflammatory, and protein W69163 biological processes ranging from in Molecular Biology, 2000, vol. 138: infectious disorders, designated SLC hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer (secondary leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. lymphoid this family are involved in a similar- Power. chemokine) ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CC GeneSeq WO9826071 Chemokines are a family of related Chemokine activities can be determined Cancer and chemokine ELC Accession small, secreted proteins involved in using assays known in the art: Methods infectious diseases, protein W62542 biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly herpes hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. virus leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human DVic-1 GeneSeq Wo9823750 Chemokines are a family of related Chemokine activities can be determined Abnormal prolifera- C-C chemokine Accession small, secreted proteins involved in using assays known in the art: Methods tion, regeneration, W60649 biological processes ranging from in Molecular Biology, 2000, vol. 138: degeneration, and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. atrophy disorders, leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. including cancer this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human C-C GeneSeq WO9823750 Chemokines are a family of related Chemokine activities can be determined Immune disorders, chemokine Accession small, secreted proteins involved in using assays known in the art: Methods cell proliferation DGWCC W60650 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, cancer hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human STCP-1 GeneSeq WO9824907 Chemokines are a family of related Chemokine activities can be determined Immune disorders, Accession small, secreted proteins involved in using assays known in the art: Methods particularly T cell W62783 biological processes ranging from in Molecular Biology, 2000, vol. 138: related disorders, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. viral infection, and leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. inflammation, this family are involved in a similar- Power. especially joint ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Exodua protein GeneSeq WO9821330 Chemokines are a family of related Chemokine activities can be determined Immune and inflam- Accession small, secreted proteins involved in using assays known in the art: Methods matory disorders, W61279 biological processes ranging from in Molecular Biology, 2000, vol. 138: angiogenesis, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer, and prolif- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. eration disorders, this family are involved in a similar- Power. particularly ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. myeloproliferative cluding inflammation, allergy, tissue diseases rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9814581 Chemokines are a family of related Chemokine activities can be determined Cancer and de- Chr19Kine Acession small, secreted proteins involved in using assays known in the art: Methods generative disorders protein W50887 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human T cell GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Immune, inflam- mixed Accession 5,780,268 small, secreted proteins involved in using assays known in the art: Methods matory, and lymphocyte W58703 biological processes ranging from in Molecular Biology, 2000, vol. 138: infectious disorders, reaction hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer expressed leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. chemokine this family are involved in a similar- Power. (TMEC) ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human 6CKine GeneSeq W09814581 Chemokines are a family of related Chemokine activities can be determined Cancer and de- protein Accession small, secreted proteins involved in using assays known in the art: Methods generative disorders W50885 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. human liver and GeneSeq WO9817800 Chemokines are a family of related Chemokine activities can be determined Immune, inflam- activation Accession small, secreted proteins involved in using assays known in the art: Methods matory, and regulated W57475 biological processes ranging from in Molecular Biology, 2000, vol. 138: infectious disorders, chemokine hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer (LARC) leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES GeneSeq WO9744462 Chemokines are a family of related Chemokine activities can be determined Infectious diseases, peptide Accession small, secreted proteins involved in using assays known in the art: Methods particularly HIV W29538 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES 8-68 GeneSeq WO9744462 Chemokines are a family of related Chemokine activities can be determined Infectious diseases, Accession small, secreted proteins involved in using assays known in the art: Methods particularly HIV W29529 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. RANTES 9-68 GeneSeq WO9744462 Chemokines are a family of related Chemokine activities can be determined Infectious diseases, Accession small, secreted proteins involved in using assays known in the art: Methods particularly HIV W29528 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9811226 Chemokines are a family of related Chemokine activities can be determined Abnormal prolifera- chemokine Accession small, secreted proteins involved in using assays known in the art: Methods tion, regeneration, protein 331D5 W59433 biological processes ranging from in Molecular Biology, 2000, vol. 138: degeneration, or hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. atrophy, including leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. cancer this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9811226 Chemokines are a family of related Chemokine activities can be determined Abnormal prolifera- chemokine Accession small, secreted proteins involved in using assays known in the art: Methods tion, regeneration, protein 61164 W59430 biological processes ranging from in Molecular Biology, 2000, vol. 138: degeneration, or hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. atrophy, including leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. cancer this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9809171 Chemokines are a family of related Chemokine activities can be determined Immune, MCP-4 Accession small, secreted proteins involved in using assays known in the art: Methods Inflammatory, and W56690 biological processes ranging from in Molecular Biology, 2000, vol. 138: infectious diseases hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human stromal GeneSeq FR2751658 Chemokines are a family of related Chemokine activities can be determined HIV infections cell-derived Accession small, secreted proteins involved in using assays known in the art: Methods chemokine, W50766 biological processes ranging from in Molecular Biology, 2000, vol. 138: SDF-1 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Thymus GeneSeq WO9801557 Chemokines are a family of related Chemokine activities can be determined Immune and inflam- expressed Accession small, secreted proteins involved in using assays known in the art: Methods matory disorders chemokine W44397 biological processes ranging from in Molecular Biology, 2000, vol. 138: (TECK) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9801557 Chemokines are a family of related Chemokine activities can be determined Immune and inflam- chemokine Accession small, secreted proteins involved in using assays known in the art: Methods matory disorders MIP-3alpha W44398 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9801557 Chemokines are a family of related Chemokine activities can be determined Immune and inflam- chemokine Accession small, secreted proteins involved in using assays known in the art: Methods matory disorders MIP-3beta W44399 biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9802459 Chemokines are a family of related Chemokine activities can be determined Immune disorders, monocyte Accession small, secreted proteins involved in using assays known in the art: Methods respiratory chemotactic W42072 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, cancer proprotein hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. (MCPP) leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. sequence this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage- GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Immune, and derived Accessions 5,688,927/U.S. small, secreted proteins involved in using assays known in the art: Methods inflammatory chemokine W40811 and Pat. No. biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, cancer (MDC) Y24414 5,932,703 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Immune and inflam- derived Accession Y24416 5,932,703 small, secreted proteins involved in using assays known in the art: Methods matory disorders chemokine biological processes ranging from in Molecular Biology, 2000, vol. 138: analogue MDC- hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. eyfy leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Immune and inflam- derived Accession Y24413 5,932,703 small, secreted proteins involved in using assays known in the art: Methods matory disorders chemokine biological processes ranging from in Molecular Biology, 2000, vol. 138: analogue MDC hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. (n + 1) leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Macrophage GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Immune and inflam- derived Accession Y24415 5,932,703 small, secreted proteins involved in using assays known in the art: Methods matory disorders chemokine biological processes ranging from in Molecular Biology, 2000, vol. 138: analogue MDC- hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. yl leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human type CC GeneSeq JP11243960 Chemokines are a family of related Chemokine activities can be determined Allergic diseases chemokine Accession Y43178 small, secreted proteins involved in using assays known in the art: Methods and HIV infection eotaxin 3 biological processes ranging from in Molecular Biology, 2000, vol. 138: protein hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. sequence leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human MCP-3 GeneSeq WO9946392 Chemokines are a family of related Chemokine activities can be determined Cancer and immune and human Acession Y29893 small, secreted proteins involved in using assays known in the art: Methods disorders, Muc-1 core biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly HIV epitope (VNT) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. infection fusion protein leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human IP-10 GeneSeq WO9946392 Chemokines are a family of related Chemokine activities can be determined Cancer and immune and human Accession Y29894 small, secreted proteins involved in using assays known in the art: Methods disorders, Muc-1 core biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly HIV epitope (VNT) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. infection fusion protein leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human IP-10 GeneSeq W09946392 Chemokines are a family of related Chemokine activities can be determined Cancer and immune and HIV-1 gp Accession Y29897 small, secreted proteins involved in using assays known in the art: Methods disorders, 120 hyper- biological processes ranging from in Molecular Biology, 2000, vol. 138: particularly HIV variable region hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. infection fusion protein leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9936540 Chemokines are a family of related Chemokine activities can be determined Breast disease, mammary Accessions small, secreted proteins involved in using assays known in the art: Methods including cancer associated Y29092 and biological processes ranging from in Molecular Biology, 2000, vol. 138: chemokine Y29093 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. (MACK) leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. protein this family are involved in a similar- Power. Full-Length and ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. Mature cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Tim-1 protein GeneSeq WO9933990 Chemokines are a family of related Chemokine activities can be determined Inflammation due to Accession small, secreted proteins involved in using assays known in the art: Methods stimuli such as heart Y28290 biological processes ranging from in Molecular Biology, 2000, vol. 138: attacks and stroke, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. infection, physical leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. trauma, UV or this family are involved in a similar- Power. ionizing radiation, ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. burns, frostbite or cluding inflammation, allergy, tissue corrosive chemicals rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human Lkn-1 GeneSeq WO9928473 Chemokines are a family of related Chemokine activities can be determined HIV infection and Full-Length and Accessions and small, secreted proteins involved in using assays known in the art: Methods cancer, particularly Mature protein Y17280, Y17274, WO9928472 biological processes ranging from in Molecular Biology, 2000, vol. 138: leukemia Y17281, and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Y17275 leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq WO9920759 Chemokines are a family of related Chemokine activities can be determined Inhibit or stimulate modified Accession Y05818 small, secreted proteins involved in using assays known in the art: Methods angiogenesis, inhibit chemokine met- biological processes ranging from in Molecular Biology, 2000, vol. 138: the binding of HIV hSDF-1 alpha hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq WO9920759 Chemokines are a family of related Chemokine activities can be determined Inhibit or stimulate modified Accession Y05819 small, secreted proteins involved in using assays known in the art: Methods angiogenesis, inhibit chemokine met- biological processes ranging from in Molecular Biology, 2000, vol. 138: the binding of HIV, hSDF-1 beta hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. antiinflammatory; leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. immunosuppressant this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq WO9920759 Chemokines are a family of related Chemokine activities can be determined Inhibit or stimulate modified Accession Y05820 small, secreted proteins involved in using assays known in the art: Methods angiogenesis, inhibit chemokine biological processes ranging from in Molecular Biology, 2000, vol. 138: the binding of HIV, GroHEK/hSDF- hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. antiinflammatory; 1alpha leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. immunosuppressant this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. N-terminal GeneSeq WO9920759 Chemokines are a family of related Chemokine activities can be determined Inhibit or stimulate modified Accession Y05821 small, secreted proteins involved in using assays known in the art: Methods angiogenesis, inhibit chemokine biological processes ranging from in Molecular Biology, 2000, vol. 138: the binding of HIV, GroHEK/hSDF- hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. antiinflammatory; 1beta. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. immunosuppressant this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related Chemokine activities can be determined Increase or enhance Eotaxin Accession small, secreted proteins involved in using assays known in the art: Methods an inflammatory Y14230 biological processes ranging from in Molecular Biology, 2000, vol. 138: response, an hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. immune response leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. orhaematopoietic this family are involved in a similar- Power. cell-associated ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. activity; treat a cluding inflammation, allergy, tissue vascular indication; rejection, viral infection, and tumor Cancer; enhance biology. The chemokines exert their wound healing, to effects by acting on a family of prevent or treat seven transmembrane G-protein asthma, organ coupled receptors. Over 40 human transplant rejction, chemokines have been described, rheumatoid which bind to ~17 receptors thus far arthritis or allergy identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related Chemokine activities can be determined Immune disorders, hMCP1a Accession small, secreted proteins involved in using assays known in the art: Methods Vascular disorders, Y14225 biological processes ranging from in Molecular Biology, 2000, vol. 138: Wound healing, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer, prevent leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. organ transplant this family are involved in a similar- Power. rejection, Increase or ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. enhance an inflam- cluding inflammation, allergy, tissue matory response, rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related Chemokine activities can be determined Immune disorders, hMCP1b Accession small, secreted proteins involved in using assays known in the art: Methods Vascular disorders, Y14226 biological processes ranging from in Molecular Biology, 2000, vol. 138: Wound healing, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer, prevent leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. organ transplant this family are involved in a similar- Power. rejection, Increase or ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. enhance an inflam- cluding inflammation, allergy, tissue matory response, rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related Chemokine activities can be determined Immune disorders, hSDF1b Accession small, secreted proteins involved in using assays known in the art: Methods Vascular disorders, Y14228 biological processes ranging from in Molecular Biology, 2000, vol. 138: Wound healing, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer, prevent leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. organ transplant this family are involved in a similar- Power. rejection, Increase or ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. enhance an inflam- cluding inflammation, allergy, tissue matory response, rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related Chemokine activities can be determined Immune disorders, hIL-8 Accession small, secreted proteins involved in using assays known in the art: Methods Vascular disorders, Y14229 biological processes ranging from in Molecular Biology, 2000, vol. 138: Wound healing, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer, prevent leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. organ transplant this family are involved in a similar- Power. rejection, Increase or ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ; enhance an inflam- cluding inflammation, allergy, tissue and Holmes et al (1991) Science 253, matory response, rejection, viral infection, and tumor 1278-80. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related Chemokine activities can be determined Immune disorders, hMCP1 Accession small, secreted proteins involved in using assays known in the art: Methods Vascular disorders, Y14222 biological processes ranging from in Molecular Biology, 2000, vol. 138: Wound healing, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer, prevent leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. organ transplant this family are involved in a similar- Power. rejection, Increase or ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. enhance an inflam- cluding inflammation, allergy, tissue matory response, rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related Chemokine activities can be determined Immune disorders, hMCP2 Accession small, secreted proteins involved in using assays known in the art: Methods Vascular disorders, Y14223 biological processes ranging from in Molecular Biology, 2000, vol. 138: Wound healing, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer, prevent leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. organ transplant this family are involved in a similar- Power. rejection, Increase or ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. enhance an inflam- cluding inflammation, allergy, tissue matory response, rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokine GeneSeq WO9912968 Chemokines are a family of related Chemokine activities can be determined Immune disorders, hMCP3 Accession small, secreted proteins involved in using assays known in the art: Methods Vascular disorders, Y14224 biological processes ranging from in Molecular Biology, 2000, vol. 138: Wound healing, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. cancer, prevent leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. organ transplant this family are involved in a similar- Power. rejection, Increase or ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. enhance an inflam- cluding inflammation, allergy, tissue matory response, rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. C-C chemokine, GeneSeq EP905240 Chemokines are a family of related Chemokine activities can be determined Inflammatory, MCP2 Accession small, secreted proteins involved in using assays known in the art: Methods Immune and Y05300 biological processes ranging from in Molecular Biology, 2000, vol. 138: infectious diseases; hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. pulmonary diseases leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and skin disorders; this family are involved in a similar- Power. tumours, and ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. angiogenesis-and cluding inflammation, allergy, tissue haematopoiesis- rejection, viral infection, and tumor related diseases biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Wild type GeneSeq EP906954 Chemokines are a family of related Chemokine activities can be determined Inflammatory, monocyte Accession small, secreted proteins involved in using assays known in the art: Methods Immune and chemotactic Y07233 biological processes ranging from in Molecular Biology, 2000, vol. 138: infectious diseases; protein 2 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. pulmonary diseases leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and skin disorders; this family are involved in a similar- Power. tumours, and ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. angiogenesis-and cluding inflammation, allergy, tissue haematopoiesis- rejection, viral infection, and tumor related diseases biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Truncated GeneSeq EP906954 Chemokines are a family of related Chemokine activities can be determined Inflammatory, monocyte Accession small, secreted proteins involved in using assays known in the art: Methods Immune and chemotactic Y07234 biological processes ranging from in Molecular Biology, 2000, vol. 138: infectious diseases; protein 2 (6-76) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. pulmonary diseases leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and skin disorders; this family are involved in a similar- Power, tumours, and ly diverse range of pathologies in- Humana Press Inc., Totowa, NJ angiogenesis-and cluding inflammation, allergy, tissue haematopoiesis- rejection, viral infection, and tumor related diseases biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Truncated GeneSeq EP905241; Chemokines are a family of related Chemokine activities can be determined Inflammatory, RANTES Accessions EP906954 small, secreted proteins involved in using assays known in the art: Methods immune and protein (3-68) Y07236 and biological processes ranging from in Molecular Biology, 2000, vol. 138: infectious diseases; Y07232 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. pulmonary diseases leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and skin disorders; this family are involved in a similar- Power, tumours, and ly diverse range of pathologies in- Humana Press Inc., Totowa, NJ angiogenesis-and cluding inflammation, allergy, tissue haematopoiesis- rejection, viral infection, and tumor related diseases biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Wild type GeneSeq EP905241 Chemokines are a family of related Chemokine activities can be determined Inflammatory, monocyte Accession small, secreted proteins involved in using assays known in the art: Methods immune and chemotactic Y07237 biological processes ranging from in Molecular Biology, 2000, vol. 138: infectious diseases; protein 2 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. pulmonary diseases leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and skin disorders; this family are involved in a similar- Power, tumours, and ly diverse range of pathologies in- Humana Press Inc., Totowa, NJ angiogenesis-and cluding inflammation, allergy, tissue haematopoiesis- rejection, viral infection, and tumor related diseases biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Truncated GeneSeq EP905241 Chemokines are a family of related Chemokine activities can be determined Inflammatory, monocyte Accession small, secreted proteins involved in using assays known in the art: Methods immune and chemotactic Y07238 biological processes ranging from in Molecular Biology, 2000, vol. 138: infectious diseases; protein 2 (6-76) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. pulmonary diseases leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and skin disorders; this family are involved in a similar- Power, tumours, and ly diverse range of pathologies in- Humana Press Inc., Totowa, NJ angiogenesis-and cluding inflammation, allergy, tissue haematopoiesis- rejection, viral infection, and tumor related diseases biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A partial GeneSeq EP897980 Chemokines are a family of related Chemokine activities can be determined Soluble CXCR4B CXCR4B Accession small, secreted proteins involved in using assays known in the art: Methods receptor polypep- protein W97363 biological processes ranging from in Molecular Biology, 2000, vol. 138: tides may be useful hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. for inhibiting leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. chemokine activities this family are involved in a similar- Power, and viral infection. ly diverse range of pathologies in- Humana Press Inc., Totowa, NJ cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Interferon GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, gamma- Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- inducible W96709 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune protein (IP-10) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power, Musco-skeletal ly diverse range of pathologies in- Humana Press Inc., Totowa, NJ disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A monokine GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, induced by Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- gamma- W96710 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune interferon hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- (MIG) leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power, Musco-skeletal ly diverse range of pathologies in- Humana Press Inc., Totowa, NJ disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Interleukin-8 GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, (IL-8) protein. Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- W96711 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power. Musco-skeletal ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ; disorders cluding inflammation, allergy, tissue and Holmes et al (1991) Science 253, rejection, viral infection, and tumor 1278-80. biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Epithelial GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, neutrophil Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- activating W96712 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune protein-78 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- (ENA-78) leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power, Musco-skeletal ly diverse range of pathologies in- Humana Press Inc., Totowa, NJ disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Growth related GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, oncogene-alpha Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- (GRO-alpha). W96713 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power, Musco-skeletal ly diverse range of pathologies in- Humana Press Inc., Totowa, NJ disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Growth related GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, oncogene-beta Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- (GRO-beta). W96714 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power. Musco-skeletal ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Growth related GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, oncogene- Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- gamma W96715 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune (GRO-gamma) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power. Musco-skeletal ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A platelet basic GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, protein (PBP) Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- W96716 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power. Musco-skeletal ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Connective GeneSeqAc- U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, tissue activating cession S96717 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- protein-III biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune (CTAP-III) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power. Musco-skeletal ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Beta-thrombo- GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, globulin protein Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- (beta-TG) W96718 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power. Musco-skeletal ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Neutrophil GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, activating Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- peptide-2 W96719 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune (NAP-2) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power. Musco-skeletal ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Granulocyte GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Angiogenesis, chemotactic Accession 5,871,723 small, secreted proteins involved in using assays known in the art: Methods Cancer, Inflam- protein-2 W96720 biological processes ranging from in Molecular Biology, 2000, vol. 138: matory and Immune (GCP-2) hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, Cardio- leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Vascular disorders, this family are involved in a similar- Power. Musco-skeletal ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. disorders cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq EP887409 Chemokines are a family of related Chemokine activities can be determined Immune disorders, chemokine Accession small, secreted proteins involved in using assays known in the art: Methods viral, parasitic, MIG-beta W90124 biological processes ranging from in Molecular Biology, 2000, vol. 138: fungal or bacterial protein hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. infections, Cancer; leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. autoimmune this family are involved in a similar- Power. diseases or ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. transplant rejection cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO9854326 Chemokines are a family of related Chemokine activities can be determined Immune disorders, ZCHEMO-8 Accession small, secreted proteins involved in using assays known in the art: Methods cancer, myelopoietic W82716 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. autoimmune leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders and this family are involved in a similar- Power. immunodeficiencies, ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. Inflammatory and cluding inflammation, allergy, tissue infectious diseases, rejection, viral infection, and tumor Vascular disorders, biology. The chemokines exert their wound healing effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human Act-2 GeneSeq WO9854326 Chemokines are a family of related Chemokine activities can be determined Immune disorders, protein Accession small, secreted proteins involved in using assays known in the art: Methods cancer, myelopoietic W82717 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. autoimmune leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders and this family are involved in a similar- Power. immunodeficiencies, ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. Inflammatory and cluding inflammation, allergy, tissue infectious diseases, rejection, viral infection, and tumor Vascular disorders, biology. The chemokines exert their wound healing effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human SISD GeneSeq WO9854326 Chemokines are a family of related Chemokine activities can be determined Immune disorders, protein Acession small, secreted proteins involved in using assays known in the art: Methods cancer, myelopoietic W82720 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. autoimmune leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders and this family are involved in a similar- Power. immunodeficiencies, ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. Inflammatory and cluding inflammation, allergy, tissue infectious diseases, rejection, viral infection, and tumor Vascular disorders, biology. The chemokines exert their wound healing effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human M110 GeneSeq WO9854326 Chemokines are a family of related Chemokine activities can be determined Immune disorders, protein Accession small, secreted proteins involved in using assays known in the art: Methods cancer, myelopoietic W82721 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. autoimmune leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders and this family are involved in a similar- Power. immunodeficiencies, ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. Inflammatory and cluding inflammation, allergy, tissue infectious diseases, rejection, viral infection, and tumor Vascular disorders, biology. The chemokines exert their wound healing effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokines are a family of related Human M11A GeneSeq W09854326 Chemokines are a family of related Chemokine activities can be determined Immune disorders, protein Accession small, secreted proteins involved in using assays known in the art: Methods cancer, myelopoietic W82722 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. autoimmune leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders and this family are involved in a similar- Power. immunodeficiencies, ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. Inflammatory and cluding inflammation, allergy, tissue infectious diseases, rejection, viral infection, and tumor Vascular disorders, biology. The chemokines exert their wound healing effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Chemokines are a family of related Human CCC3 GeneSeq WO9854326 Chemokines are a family of related Chemokine activities can be determined Immune disorders, protein Accession small, secreted proteins involved in using assays known in the art: Methods cancer, myelopoietic W82723 biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. autoimmune leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders and this family are involved in a similar- Power. immunodeficiencies, ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. Inflammatory and cluding inflammation, allergy, tissue infectious diseases, rejection, viral infection, and tumor Vascular disorders, biology. The chemokines exert their wound healing effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A human L105 GeneSeq WO9856818 Chemokines are a family of related Chemokine activities can be determined Cancer, wound chemokine Accession small, secreted proteins involved in using assays known in the art: Methods healing designated W87588 biological processes ranging from in Molecular Biology, 2000, vol. 138: huL105_3. hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A human L105 GeneSeq WO9856818 Chemokines are a family of related Chemokine activities can be determined Cancer, wound chemokine Accession small, secreted proteins involved in using assays known in the art: Methods healing designated W87589 biological processes ranging from in Molecular Biology, 2000, vol. 138: huL105_7. hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human mature GeneSeq WO9848828 Chemokines are a family of related Chemokine activities can be determined Infectious diseases, gro-alpha Accession small, secreted proteins involved in using assays known in the art: Methods sepsis polypeptide W81498 biological processes ranging from in Molecular Biology, 2000, vol. 138: used to treat hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. sepsis leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human mature GeneSeq WO9848828 Chemokines are a family of related Chemokine activities can be determined Infectious diseases, gro-gamma Accession small, secreted proteins involved in using assays known in the art: Methods sepsis polypeptide W81500 biological processes ranging from in Molecular Biology, 2000, vol. 138: used to treat hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. sepsis leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human thymus GeneSeq WO0053635 Chemokines are a family of related Chemokine activities can be determined Inflammatory expressed Accessions small, secreted proteins involved in using assays known in the art: Methods disorders, cancer, chemokine B19607 and biological processes ranging from in Molecular Biology, 2000, vol. 138: Immune and TECK and B19608 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. vascular disorders TECK variant leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine Accession B15791 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, SDF1alpha biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine Accession B15793 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, GROalpha biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine Accession B15794 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, eotaxin biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine MIG Accession B15803 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine PF4 Accession B15804 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine I- Accession B15805 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, 309 biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine Accession B15806 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, HCC-1 biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine C10 Accession B15807 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine Accession B15808 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, CCR-2 biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine Accession B15809 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, ENA-78 biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine Accession B15810 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, GRObeta biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine IP- Accession B15811 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, 10 biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine Accession B15812 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, SDF1beta biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine Accession B15813 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, GRO alpha biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0042071 Chemokines are a family of related Chemokine activities can be determined Autoimmune chemokine Accession B15831 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune, MIP1beta biological processes ranging from in Molecular Biology, 2000, vol. 138: Vascular and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Inflammatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. A human C-C GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Cancer chemokine Accession B07939 6,096,300 small, secreted proteins involved in using assays known in the art: Methods designated biological processes ranging from in Molecular Biology, 2000, vol. 138: exodus hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Chemotaxis, Gene chemokine Accession Y96922 6,084,071 small, secreted proteins involved in using assays known in the art: Methods Therapy, Wound L105_7 biological processes ranging from in Molecular Biology, 2000, vol. 138: healing hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Chemotaxis, Gene chemokine Accession Y96923 6,084,071 small, secreted proteins involved in using assays known in the art: Methods Therapy, Wound L105_3 biological processes ranging from in Molecular Biology, 2000, vol. 138: healing hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0038706 Chemokines are a family of related Chemokine activities can be determined Cancer, Vascular secondary Accession B01434 small, secreted proteins involved in using assays known in the art: Methods and Immune lymphoid biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders chemokine hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. (SLC) leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human non- GeneSeq WO0029439 Chemokines are a family of related Chemokine activities can be determined Immune and ELR CXC Accession Y96310 small, secreted proteins involved in using assays known in the art: Methods Inflammatory chemokine biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, Cancer, H174 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. Haemostatic and leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. thrombolytic activity this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human non- GeneSeq WO0029439 Chemokines are a family of related Chemokine activities can be determined Immune and ELR CXC Accession Y96311 small, secreted proteins involved in using assays known in the art: Methods Inflammatory chemokine biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, Cancer, IP10 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. haemostatic and leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. thrombolytic activity this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human non- GeneSeq WO0029439 Chemokines are a family of related Chemokine activities can be determined Immune and ELR CXC Accession Y96313 small, secreted proteins involved in using assays known in the art: Methods Inflammatory chemokine biological processes ranging from in Molecular Biology, 2000, vol. 138: disorders, Cancer, Mig hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. haemostatic and leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. thrombolytic activity this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0028035 Chemokines are a family of related Chemokine activities can be determined Cancer, wound chemokine Accession Y96280 small, secreted proteins involved in using assays known in the art: Methods healing, Ckbeta-7 biological processes ranging from in Molecular Biology, 2000, vol. 138: inflammatory and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. immunoregulatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0028035 Chemokines are a family of related Chemokine activities can be determined Cancer, wound chemokine Accession Y96281 small, secreted proteins involved in using assays known in the art: Methods healing, MIP-1alpha biological processes ranging from in Molecular Biology, 2000, vol. 138: inflammatory and hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. immunoregulatory leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human mature GenSeq WO0028035 Chemokines are a family of related Chemokine activities can be determined Cancer, wound chemokine Accession Y96282 small, secreted proteins involved in using assays known in the art: Methods healing, Ckbeta-7 biological processes ranging from in Molecular Biology, 2000, vol. 138: inflammatory and (optionally hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. immunoregulatory truncated) leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. disorders this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq WO0018431 Chemokines are a family of related Chemokine activities can be determined Soluble CXCR3 chemokine Accession Y79372 small, secreted proteins involved in using assays known in the art: Methods polypeptides may be receptor biological processes ranging from in Molecular Biology, 2000, vol. 138: useful for inhibiting CXCR3 hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. chemokine activities leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. and viral infection. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Neurological neurotactin Accession Y53259 6,043,086 small, secreted proteins involved in using assays known in the art: Methods disorders, Immune chemokine like biological processes ranging from in Molecular Biology, 2000, vol. 138: and respiratory domain hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CC type GeneSeq JP11302298 Chemokines are a family of related Chemokine activities can be determined Cancer and chemokine Accession Y57771 small, secreted proteins involved in using assays known in the art: Methods infectious diseases interleukin C biological processes ranging from in Molecular Biology, 2000, vol. 138: hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. this family are involved in a similar- Power. ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Human CKbeta- GeneSeq U.S. Pat. No. Chemokines are a family of related Chemokine activities can be determined Cancer, Auto- 9 Accession B50860 6,153,441 small, secreted proteins involved in using assays known in the art: Methods immune and biological processes ranging from in Molecular Biology, 2000, vol. 138: inflammatory hematopoiesis, angiogenesis, and Chemokine Protocols. Edited by: A. E. disorders, leukocyte trafficking. Members of I. Proudfoot, T. N. C. Wells, and C. A. Cardiovascular this family are involved in a similar- Power. disorders ly diverse range of pathologies in- © Humana Press Inc., Totowa, NJ. cluding inflammation, allergy, tissue rejection, viral infection, and tumor biology. The chemokines exert their effects by acting on a family of seven transmembrane G-protein coupled receptors. Over 40 human chemokines have been described, which bind to ~17 receptors thus far identified. Preproapolipo- GeneSeq WO9637608 Apoa-1 participates in the reverse Lipid binding activity can be Useful for cardio- protein “paris” Accession transport of cholesterol from tissues determined using assays known in the vascular disorders, variant W08602 to the liver for excretion by art, such as, for example, the cholesterol promoting cholesterol efflux from Cholesterol Efflux Assays of disorders, and tissues and by acting as a cofactor Takahaski et al., P. N. A. S., Vol. 96, Hyperlipidaemia for the lecithin cholesterol Issue 20, 11358-11363, Sep. 28, 1999. acyltransferase (Icat). Preproapolipo- 5,721,114 Apoa-1 participates in the reverse Lipid binding activity can be Useful for cardio- protein transport of cholesterol from tissues determined using assays known in the vascular disorders, “milano” to the liver for excretion by art, such as, for example, the cholesterol variant promoting cholesterol efflux from Cholesterol Efflux Assays of disorders, and tissues and by acting as a cofactor Takahaski et al., P. N. A. S., Vol. 96, Hyperlipidaemia for the lecithin cholesterol Issue 20, 11358-11363, Sep. 28, 1999. acyltransferase (Icat). Glycodelin-A; GeneSeq WO9628169 Naturally produced female Glycodelin-A activity can be Naturally derived Progesterone- Accession contraceptive that is removed determined using the hemizona assay as contraceptive useful associated W00289 rapidly from the body following 2-3 described in Oehninger, S., Coddington, for the prevention of endometrial days production. Uses include C. C., Hodgen, G. D., and Seppala, M pregnancy. protein contraception (1995) Fertil. Steril. 63, 377-383. NOGO-A Genbank NOGO polypeptides are potent Inhibition of Neurite outgrowth. NOGO-A polypep- Accession inhibitors of neurite growth. Antagonists to NOGO polypeptides tide antagonists are CAB99248 may promote the outgrowth of neurites, useful for the pro- thus inducing regeneration of neurons. motion of neural growth, which could be useful in the treatment of neural disorders and dys- function due to de- generative diseases or trauma; useful in the treatment of neo- plastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. NOGO-B Genbank NOGO polypeptides are potent Inhibition of Neurite outgrowth. NOGO-B polypep- Accession inhibitors of neurite growth. Antagonists to NOGO polypeptides tide antagonists are CAB99249 may promote the outgrowth of neurites, useful for the pro- thus inducing regeneration of neurons. motion of neural growth, which could be useful in the treatment of neural disorders and dys- function due to de- generative diseases or trauma; useful in the treatment of neo- plastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. NOGO-C Genbank NOGO polypeptides are potent Inhibition of Neurite outgrowth. NOGO-C polypep- Accession inhibitors of neurite growth. Antagonists to NOGO polypeptides tide antagonists are CAB99250 may promote the outgrowth of neurites, useful for the pro- thus inducing regeneration of neurons. motion of neural growth, which could be useful in the treatment of neural disorders and dys- function due to de- generative diseases or trauma; useful in the treatment of neo- plastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. NOGO-66 Genbank NOGO polypeptides are potent Inhibition of Neurite outgrowth by NOGO-66 receptor Receptor Accession inhibitors of neurite growth, and are mediating the biological effects of polypeptides are AAG53612 thought to mediate their effects NOGO polypeptides. Soluble NOGO- useful for the through the NOGO-66 Receptor. 66 receptor polypeptides may promote promotion of neural the outgrowth of neurites, thus inducing growth, which could regeneration of neurons. be useful in the treatment of neural disorders and dys- function due to de- generative diseases or trauma; useful in the treatment of neo- plastic diseases of the CNS; induce regeneration of neurons or to promote the structural plasticity of the CNS. Antibodies U.S. Pat. No. These antibodies are useful for the Collapsin activity, which is thought to Useful for the pro- specific for 5,416,197 promotion of neurite outgrowth inhibit the outgrowth of neurites, can be motion of neural collapsin assayed in the presence of antibodies growth, which could specific for collapsing using assays be useful in the known in the art, such as, for example, treatment of neural the collapse assay disclosed by Luo et disorders and dys- al., Cell 1993 Oct 22; 75(2): 217-27 function due to de- generative diseases or trauma. Humanized WO9845331 These agents have anti-inflammatory VEGF activity can be determined using Promotion of growth Anti-VEGF and anti-cancer applications assays known in the art, such as those and proliferation of Antibodies, and disclosed in International Publication cells, such as fragments No. WO0045835, for example. vascular endothelial thereof cells. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer Humanized WO0029584 These agents have anti-inflammatory VEGF activity can be determined using Promotion of growth Anti-VEGF and anti-cancer applications assays known in the art, such as those and proliferation of Antibodies, and disclosed in International Publication cells, such as fragments No. WO0045835, for example. vascular endothelial thereof cells. Hematopoietic and immune dis- orders. Antagonists may be useful as anti-angiogenic agents, and may be applicable for cancer Membrane GeneSeq. WO9963088 Cancer, Immune Disorders These proteins can be used for linking Activities can be bound proteins Accession bioactive molecules to cells and for determined using Y66631-Y66765 modulating biological activities of cells, assay known in the using the polypeptides for specific art, such as, for targeting. The polypeptide targeting can example, the assays be used to kill the target cells, e.g. for disclosed in the treatment of cancers. These proteins International are useful for the treatment of immune Publication system disorders. No.WO0121658. Secreted and GenSeq WO0053756 Cancer, Immune Disorders These proteins can be used for linking Activities can be Transmembrane Accession bioactive molecules to cells and for determined using polypeptides B44241-B44334 modulating biological activities of cells, assay known in the using the polypeptides for specific art, such as, for targeting. The polypeptide targeting can example, the assays be used to kill the target cells, e.g. for disclosed in the treatment of cancers. These proteins International are useful for the treatment of immune Publication system disorders. No.WO0121658. Secreted and GeneSeq WO9946281 Cancer, Immune Disorders These proteins can be used for linking Activities can be Transmembrane Accession bioactive molecules to cells and for determined using polypeptides Y41685-Y41774 modulating biological activities of cells, assay known in the using the polypeptides for specific art, such as, for targeting. The polypeptide targeting can example, the assays be used to kill the target cells, e.g. for disclosed in the treatment of cancers. These proteins International are useful for the treatment of immune Publication system disorders. No.WO0121658. Conjugation and Coupling

The present invention provides therapeutic agents comprising an elastic peptide component and a therapeutic component, such as therapeutic proteins listed in herein, including Table 1, as well as a GLP-1 receptor agonists, insulin, Factor VII/VIIa, and functional analogs as described. Such agents may be prepared by recombinant technology and/or chemical coupling (e.g., conjugation).

A recombinantly-produced elastic peptide fusion protein, in accordance with certain embodiments of the invention, includes the elastic peptide component and the therapeutic component associated with one another by genetic fusion. For example, the fusion protein may be generated by translation of a polynucleotide encoding the therapeutic component cloned in-frame with the elastic peptide component (or vice versa). Such an elastic peptide fusion protein may contain one or more copies of the therapeutic component attached to the N-terminus and/or the C-terminus of the elastic peptide component. In some embodiments, the therapeutic proteinacious component is attached to both the N- and C-terminus of the elastic peptide component and the fusion protein may contain one or more equivalents of the therapeutic component on either or both ends of the elastic peptide component.

In certain embodiments, the elastic peptide component and the therapeutic components can be fused using a linker peptide of various lengths to provide greater physical separation and allow more spatial mobility between the fused portions, and thus maximize the accessibility of the therapeutic component, for instance, for binding to its cognate receptor. The linker peptide may consist of amino acids that are flexible or more rigid. For example, a flexible linker may include amino acids having relatively small side chains, and which may be hydrophilic. Without limitation, the flexible linker may contain a stretch of glycine and/or serine residues. More rigid linkers may contain, for example, more sterically hindering amino acid side chains, such as (without limitation) tyrosine or histidine. The linker may be less than about 50, 40, 30, 20, 10, or 5 amino acid residues. The linker can be covalently linked to and between an elastic peptide component and a therapeutic component, for example, via recombinant fusion.

The linker or peptide spacer may be protease-cleavable or non-cleavable. By way of example, cleavable peptide spacers include, without limitation, a peptide sequence recognized by proteases (in vitro or in vivo) of varying type, such as Tev, thrombin, factor Xa, plasmin (blood proteases), metalloproteases, cathepsins (e.g., GFLG, etc.), and proteases found in other corporeal compartments. In some embodiments employing cleavable linkers, the fusion protein (“the therapeutic agent”) may be inactive, less active, or less potent as a fusion, which is then activated upon cleavage of the spacer in vivo. Alternatively, where the therapeutic agent is sufficiently active as a fusion, a non-cleavable spacer may be employed. The non-cleavable spacer may be of any suitable type, including, for example, non-cleavable spacer moieties having the formula [(Gly)n-Ser]m (SEQ ID NO.: 22) where n is from 1 to 4, inclusive, and m is from 1 to 4, inclusive. Alternatively, a short elastic peptide sequence different than the backbone elastic peptide could be employed instead of a linker or spacer, while accomplishing the necessary effect.

In still other embodiments, the therapeutic agent is a recombinant fusion having a therapeutic component flanked on each terminus by an elastic peptide component. At least one of said elastic peptide components may be attached via a cleavable spacer, such that the therapeutic component is inactive, but activated in vivo by proteolytic removal of a single elastic peptide component. The resulting single elastic peptide fusion being active, and having an enhanced half-life (or other property described herein) in vivo.

In other embodiments, the present invention provides chemical conjugates of the elastic peptide component and the therapeutic component. The conjugates can be made by chemically coupling an elastic peptide component to a therapeutic component by any number of methods well known in the art (See e.g. Nilsson et al., 2005, Ann Rev Biophys Bio Structure 34: 91-118). In some embodiments, the chemical conjugate can be formed by covalently linking the therapeutic component to the elastic peptide component, directly or through a short or long linker moiety, through one or more functional groups on the therapeutic proteinacious component, e.g., amine, carboxyl, phenyl, thiol or hydroxyl groups, to form a covalent conjugate. Various conventional linkers can be used, e.g., diisocyanates, diisothiocyanates, carbodiimides, bis(hydroxysuccinimide) esters, maleimide-hydroxysuccinimide esters, glutaraldehyde and the like.

Non-peptide chemical spacers can additionally be of any suitable type, including for example, by functional linkers described in Bioconjugate Techniques, Greg T. Hermanson, published by Academic Press, Inc., 1995, and those specified in the Cross-Linking Reagents Technical Handbook, available from Pierce Biotechnology, Inc. (Rockford, Ill.), the disclosures of which are hereby incorporated by reference, in their respective entireties. Illustrative chemical spacers include homobifunctional linkers that can attach to amine groups of Lys, as well as heterobifunctional linkers that can attach to Cys at one terminus, and to Lys at the other terminus.

In certain embodiments, relatively small ELP components (e.g., ELP components of less than about 30 kDa, 25 kDa, 20 kDa, 15 kDa, or 10 kDa), that do not transition at room temperature (or human body temperature, e.g., Tt>37° C.), are chemically coupled or crosslinked. For example, two relatively small ELP components, having the same or different properties, may be chemically coupled. Such coupling, in some embodiments, may take place in vivo, by the addition of a single cysteine residue at or around the C-terminus of the ELP. Such ELP components may each be fused to one or more therapeutic components, so as to increase activity or avidity at the target.

Polynucleotides, Vectors, and Host Cells

In another aspect, the invention provides polynucleotides comprising a nucleotide sequence encoding the therapeutic agent of the invention. Such polynucleotides further comprise, in addition to sequences encoding the elastic peptide and therapeutic components, one or more expression control elements. For example, the polynucleotide, may comprise one or more promoters or transcriptional enhancers, ribosomal binding sites, transcription termination signals, and polyadenylation signals, as expression control elements. The polynucleotide may be inserted within any suitable vector, which may be contained within any suitable host cell for expression.

A vector comprising the polynucleotide can be introduced into a cell for expression of the therapeutic agent. The vector can remain episomal or become chromosomally integrated, as long as the insert encoding the therapeutic agent can be transcribed. Vectors can be constructed by standard recombinant DNA technology. Vectors can be plasmids, phages, cosmids, phagemids, viruses, or any other types known in the art, which are used for replication and expression in prokaryotic or eukaryotic cells. It will be appreciated by one of skill in the art that a wide variety of components known in the art (such as expression control elements) may be included in such vectors, including a wide variety of transcription signals, such as promoters and other sequences that regulate the binding of RNA polymerase onto the promoter. Any promoter known to be effective in the cells in which the vector will be expressed can be used to initiate expression of the therapeutic agent. Suitable promoters may be inducible or constitutive. Examples of suitable promoters include the SV40 early promoter region, the promoter contained in the 3′ long terminal repeat of Rous sarcoma virus, the HSV-1 (herpes simplex virus-1) thymidine kinase promoter, the regulatory sequences of the metallothionein gene, etc., as well as the following animal transcriptional control regions, which exhibit tissue specificity and have been utilized in transgenic animals: elastase I gene control region which is active in pancreatic acinar cells; insulin gene control region which is active in pancreatic beta cells, immunoglobulin gene control region which is active in lymphoid cells, mouse mammary tumor virus control region which is active in testicular, breast, lymphoid and mast cells, albumin gene control region which is active in liver, alpha-fetoprotein gene control region which is active in liver, alpha 1-antitrypsin gene control region which is active in the liver, beta-globin gene control region which is active in erythroid cells, myelin basic protein gene control region which is active in oligodendrocyte cells in the brain, myosin light chain-2 gene control region which is active in skeletal muscle, and gonadotropin releasing hormone gene control region which is active in the hypothalamus.

Pharmaceutical Compositions

The present invention further provides pharmaceutical compositions comprising the therapeutic agents of the invention (as described above) together with a pharmaceutically acceptable carrier or excipient. Such pharmaceutical compositions may be employed in the methods of treatment as described above, for each of the therapeutic proteins, e.g., the therapeutic proteins listed in Table 1, GLP-1 receptor agonists, insulin, and Factor VII/VIIa embodiments.

The therapeutic agents of the invention may overcome certain deficiencies of peptide agents when administered (e.g., parenterally), including in some embodiments, the limitation that such peptides may be easily metabolized by plasma proteases or cleared from circulation by kidney filtration. Traditionally, the oral route of administration of peptide agents may also be problematic, because in addition to proteolysis in the stomach, the high acidity of the stomach destroys such peptide agents before they reach their intended target tissue. Peptides and peptide fragments produced by the action of gastric and pancreatic enzymes are cleaved by exo and endopeptidases in the intestinal brush border membrane to yield di- and tripeptides, and even if proteolysis by pancreatic enzymes is avoided, polypeptides are subject to degradation by brush border peptidases. Any of the peptide agents that survive passage through the stomach are further subjected to metabolism in the intestinal mucosa where a penetration barrier prevents entry into the cells. In certain embodiments, the therapeutic agents of the invention may overcome such deficiencies, and provide compositional forms having enhanced efficacy, bioavailability, therapeutic half-life, persistence, degradation assistance, etc. The therapeutic agents of the invention thus include oral and parenteral dose forms, as well as various other dose forms, by which peptide agents can be utilized in a highly effective manner. For example, in some embodiments, such agents may achieve high mucosal absorption, and the concomitant ability to use lower doses to elicit an optimum therapeutic effect.

The therapeutic agents of the present invention may be administered in smaller doses and/or less frequently than unfused or unconjugated counterparts. While one of skill in the art can determine the desirable dose in each case, a suitable dose of the therapeutic agent for achievement of therapeutic benefit, may, for example, be in a range of about 1 microgram (μg) to about 100 milligrams (mg) per kilogram body weight of the recipient per day, preferably in a range of about 10 μg to about 50 mg per kilogram body weight per day and most preferably in a range of about 10 μg to about 50 mg per kilogram body weight per day. The desired dose may be presented as one dose or two or more sub-doses administered at appropriate intervals throughout the day. These sub-doses can be administered in unit dosage forms, for example, containing from about 10 μg to about 1000 mg, preferably from about 50 μg to about 500 mg, and most preferably from about 50 μg to about 250 mg of active ingredient per unit dosage form. Alternatively, if the condition of the recipient so requires, the doses may be administered as a continuous infusion.

The mode of administration and dosage forms will of course affect the therapeutic amount of the peptide active therapeutic agent that is desirable and efficacious for a given treatment application. For example, orally administered dosages can be at least twice, e.g., 2-10 times, the dosage levels used in parenteral administration methods.

The therapeutic agents of the invention may be administered per se as well as in various forms including pharmaceutically acceptable esters, salts, and other physiologically functional derivatives thereof. The present invention also contemplates pharmaceutical formulations, both for veterinary and for human medical use, which include therapeutic agents of the invention. In such pharmaceutical and medicament formulations, the therapeutic agents can be used together with one or more pharmaceutically acceptable carrier(s) therefore and optionally any other therapeutic ingredients. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof. The therapeutic agents are provided in an amount effective to achieve the desired pharmacological effect, as described above, and in a quantity appropriate to achieve the desired daily dose.

The formulations of the therapeutic agent include those suitable for parenteral as well as non-parenteral administration, and specific administration modalities include oral, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, intrathecal, intra-articular, intra-arterial, sub-arachnoid, bronchial, lymphatic, vaginal, and intra-uterine administration. Formulations suitable for oral and parenteral administration are preferred.

When the therapeutic agent is used in a formulation including a liquid solution, the formulation advantageously can be administered orally or parenterally. When the therapeutic agent is employed in a liquid suspension formulation or as a powder in a biocompatible carrier formulation, the formulation may be advantageously administered orally, rectally, or bronchially.

When the therapeutic agent is used directly in the form of a powdered solid, the active agent can be advantageously administered orally. Alternatively, it may be administered bronchially, via nebulization of the powder in a carrier gas, to form a gaseous dispersion of the powder which is inspired by the patient from a breathing circuit comprising a suitable nebulizer device.

The formulations comprising the therapeutic agent of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation.

Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets, or lozenges, each containing a predetermined amount of the active ingredient as a powder or granules; or a suspension in an aqueous liquor or a non-aqueous liquid, such as a syrup, an elixir, an emulsion, or a draught.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, with the therapeutic agent being in a free-flowing form such as a powder or granules which optionally is mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent, or discharging agent. Molded tablets comprised of a mixture of the powdered peptide active therapeutic agent-elastic peptide construct(s) with a suitable carrier may be made by molding in a suitable machine.

A syrup may be made by adding the peptide active therapeutic agent-ELF construct(s) to a concentrated aqueous solution of a sugar, for example sucrose, to which may also be added any accessory ingredient(s). Such accessory ingredient(s) may include flavorings, suitable preservative, agents to retard crystallization of the sugar, and agents to increase the solubility of any other ingredient, such as a polyhydroxy alcohol, for example glycerol or sorbitol.

Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the therapeutic agent, which preferably is isotonic with the blood of the recipient (e.g., physiological saline solution). Such formulations may include suspending agents and thickening agents or other microparticulate systems which are designed to target the peptide active therapeutic agent to blood components or one or more organs. The formulations may be presented in unit-dose or multi-dose form.

Nasal spray formulations comprise purified aqueous solutions of the therapeutic agent with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucus membranes.

Formulations for rectal administration may be presented as a suppository with a suitable carrier such as cocoa butter, hydrogenated fats, or hydrogenated fatty carboxylic acid.

Topical formulations comprise the therapeutic agent dissolved or suspended in one or more media, such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for topical pharmaceutical formulations.

In addition to the aforementioned ingredients, the formulations of this invention may further include one or more accessory ingredient(s) selected from diluents, buffers, flavoring agents, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants), and the like.

The features and advantages of the present invention are more fully shown with respect to the following non-limiting examples.

EXAMPLES Example 1 Construction of Various ELP Component Constructs

Cloning steps were conducted in Escherichia coli strain XL1-Blue (rec A1, endA1, gyrA96, thi-1, hsdR17 (r_(k) ⁻, m_(k)+), supE44, relA1, lac[F′, proAB, /acl^(q)ZΔM15, Tn10 (Tet^(r))] (Stratagene La Jolla, Calif.). pUC19 (NEB, Beverly, Mass.) was used as the cloning vector for the ELP construction (Meyer and Chilkoti, Nat. Biotechnol., 17(11):1112-5, 1999). Modified forms of pET15b and pET24d vectors (Novagen) were used to express ELP and ELP-fusion proteins in BL21 Star (DE3) strain (F⁻, ompT, hsdS_(B) (r_(B) ⁻m_(B) ⁻), gal, dcm, me131, (DE3)) (Invitrogen Carlsbed, Calif.) or BLR(DE3) (F⁻, ompT, hsdS_(B) (r_(B) ⁻m_(B) ⁻), gal, dcm, Δ(srl-recA) 306::Tn10(TcR)(DE3)) (Novagen Madison, Wis.). Synthetic DNA oligos were purchased from Integrated DNA Technologies, Coralville, Iowa. All vector constructs were made using standard molecular biology protocols (e.g., Current Protocols in Molecular Biology, ed. Ausubel, et al., 1995).

Construction of ELP1 [V₅A₂G₃] Gene Series

The ELP1 [V₅A₂G₃] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is valine, alanine, and glycine at a relative ratio of 5:2:3.

The ELP1 [V₅A₂G₃] series monomer, ELP1 [V₅A₂G₃-10], was created by annealing four 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends (Meyer and Chilkoti, Nat. Biotechnol., 17(11):1112-5, 1999). The oligos were annealed in a 1 μM mixture of the four oligos in 50 μl IX ligase buffer (Invitrogen) to 95° C. in a heating block than the block was allowed to cool slowly to room temperature. The ELP1 [V₅A₂G₃-10]/EcoRI-HindIII DNA segment was ligated into a pUC19 vector digested with EcoRI and HindIII and CTAP dephosphorylated (Invitrogen) to form pUC19-ELP1 [V₅A₂G₃-10]. Building of the ELP1 [V₅A₂G₃] series library began by inserting ELP1 [V₅A₂G₃-10] PflMI/BglI fragment from pUC19-ELP1 [V₅A₂G₃-10] into pUC19-ELP1 [V₅A₂G₃-10] linearized with PflMI and dephosphorylated with CTAP to create pUC19-ELP1 [V₅A₂G₃-20]. pUC19-ELP1 [V₅A₂G₃-20] was then built up to pUC19-ELP1 [V₅A₂G₃-30] and pUC19-ELP1 [V₅A₂G₃-40] by ligating ELP1 [V₅A₂G₃-10] or ELP1 [V₅ A₂G₃-20] PflMI/BglI fragments respectively into PflMI digested pUC19-ELP1 [V₅A₂G₃-20]. This procedure was used to expand the ELP1 [V₅A₂G₃] series to create pUC19-ELP1 [V₅A₂G₃-60], pUC19-ELP1 [V₅A₂G₃-90] and pUC19-ELP1 [V₅A₂G₃-180] genes.

Construction of ELP1 [K₁V₂F₁] Gene Series

The ELP1 [K₁V₂F₁] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:2:1.

The ELP1 [K₁V₂F₁] series monomer, ELP1 [K₁V₂F₁-4], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends (Meyer and Chilkoti, 1999). The oligos were annealed in a 1 μM mixture of the four oligos in 50 μl 1× ligase buffer (Invitrogen) to 95° C. in a heating block then the block was allowed to cool slowly to room temperature. The ELP1 [K₁V₂F₁-4]/EcoRI-HindIII DNA segment was ligated into a pUC19 vector digested with EcoRI and HindIII and CTAP dephosphorylated (Invitrogen) to form pUC19-ELP1 [K₁V₂F₁-4]. Building of the ELP1 [K₁V₂F₁] series library began by inserting ELP1 [K₁V₂F₁-4] PflM1/Bgl1 fragment from pUC19-ELP1 [K₁ V₂F₁-4] into pUC19-ELP1 [K₁V₂F₁-4] linearized with PflM1 and dephosphorylated with CTAP to create pUC19-ELP1 [K₁V₂F₁-8]. Using the same procedure the ELP1 [K₁V₂F₁] series was doubled at each ligation to form pUC19-ELP1 [K₁V₂F₁-16], pUC19-ELP1 [K₁V₂F₁-32], pUC19-ELP1 [K₁ V₂F₁-64] and pUC19-ELP1 [K₁V₂F₁-128].

Construction of ELP1 [K₁V₇F₁] Gene Series

The ELP1 [K₁V₇F₁] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is lysine, valine, and phenylalanine at a relative ratio of 1:7:1.

The ELP1 [K₁V₇F₁] series monomer, ELP1 [K₁V₇F₁-9], was created by annealing four 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with PflMI and HindIII compatible ends. The ELP1 [K₁V₇F₁-9] DNA segment was than ligated into FY/M1/HindIII dephosphorylated PUC19-ELP1 [V₅A₂G₃-180] vector thereby substituting ELP1 [V₅A₂G₃-180] for ELP1 [K₁V₇F₁-9] to create the pUC19-ELP1 [K₁V₇F₁-9] monomer. The ELP1 [K₁V₇F₁] series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP1 [K₁V₇F₁-18], PUC19-ELP1 [K₁V₇F₁-36], pUC19-ELP1 [K₁V₇F₁-72] and pUC19-ELP1 [K₁V₇F₁-144].

Construction of ELP1 [V] Gene Series

The ELP1 [V] series designate polypeptides containing multiple repeating units of the pentapeptide VPGXG (SEQ ID NO: 3), where X is exclusively valine.

The ELP1 [V] series monomer, ELP1 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP1 [V-5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP1 [V-5] monomer. The ELP1 [V] series was created in the same manner as the ELP1 [V₅A₂G₃] series, ultimately expanding pUC19-ELP1 [V-5] to pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120].

Construction of ELP2 Gene Series

The ELP2 series designate polypeptides containing multiple repeating units of the pentapeptide AVGVP.

The ELP2 series monomer, ELP2 [5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP2 [5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP2[5] monomer. The ELP2 series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP2[10], pUC19-ELP2 [30], pUC 19-ELP2 [60] and pUC 19-ELP2 [120].

Construction of ELP3 [V] Gene Series

The ELP3 [V] series designate polypeptides containing multiple repeating units of the pentapeptide IPGXG (SEQ ID NO: 5), where X is exclusively valine.

The ELP3 [V] series monomer, ELP3 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with PfLM1 amino terminal and GGC carboxyl terminal compatible ends due to the lack of a convenient carboxyl terminal restriction site but still enable seamless addition of the monomer. The ELP3 [V-5] DNA segment was then ligated into PflM1/BglI dephosphorylated pUC19-ELP4[V-5], thereby substituting ELP4 [V-5] for ELP3 [V-5] to create the pUC19-ELP3 [V-5] monomer. The ELP3 [V] series was expanded by ligating the annealed ELP3 oligos into pUC19-ELP3[V-5] digested with PflMI. Each ligation expands the ELP3 [V] series by 5 to create ELP3 [V-10], ELP3 [V-15], etc.

Construction of the ELP4 [V] Gene Series

The ELP4 [V] series designate polypeptides containing multiple repeating units of the pentapeptide LPGXG (SEQ ID NO: 7), where X is exclusively valine.

The ELP4 [V] series monomer, ELP4 [V-5], was created by annealing two 5′ phosphorylated, PAGE purified synthetic oligos to form double stranded DNA with EcoRI and HindIII compatible ends. The ELP4 [V-5] DNA segment was than ligated into EcoRI/HindIII dephosphorylated pUC19 vector to create the pUC19-ELP4[V-5] monomer. The ELP4 [V] series was expanded in the same manner as the ELP1 [K₁V₂F₁] series to create pUC19-ELP4[V-10], pUC19-ELP4[V-30], pUC19-ELP4[V-60] and pUC19-ELP4[V-120].

The ELP genes were also inserted into other vectors such as pET15b-SD0, pET15b-SD3, pET15b-SD5, pET15b-SD6, and pET24d-SD21. The pET vector series are available from Novagen, San Diego, Calif.

The pET15b-SD0 vector was formed by modifying the pET15b vector using SD0 double-stranded DNA segment containing the multicloning restriction site (SacI-NdeI-NcoI-XhoI-SnaBI-BamHI). The SD0 double-stranded DNA segment had XbaI and BamHI compatible ends and was ligated into XbaI/BamHI linearized and 5′-dephosphorylated pET15b to form the pet15b-SD0 vector.

The pET15b-SD3 vector was formed by modifying the pET15b-SD0 vector using SD3 double-stranded DNA segment containing a SfiI restriction site upstream of a hinge region-thrombin cleavage site followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD3 double-stranded DNA segment had SacI and NdeI compatible ends and was ligated into SacI/NdeI linearized and 5′-dephosphorylated pET15b-SD0 to form the pET15b-SD3 vector.

The pET15b-SD5 vector was formed by modifying the pET15b-SD3 vector using the SD5 double-stranded DNA segment containing a SfiI restriction site upstream of a thrombin cleavage site followed by a hinge and the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD5 double-stranded DNA segment had SfiI and NdeI compatible ends and was ligated into SfiI/NdeI linearized and 5′-dephosphorylated pET15b-SD3 to form the pET15b-SD5 vector.

The pET15b-SD6 vector was formed by modifying the pET15b-SD3 vector using the SD6 double-stranded DNA segment containing a SfiI restriction site upstream of a linker region-TEV cleavage site followed by the multicloning site (NdeI-NcoI-XhoI-SnaBI-BamHI). The SD6 double-stranded DNA segment had SfiI and NheI compatible ends and was ligated into SfiI/NdeI linearized and 5′-dephosphorylated pET15b-SD3 to form the pET15b-SD6 vector.

The pET24d-SD21 vector was formed by modifying the pET24d vector using the SD21 double-stranded DNA segment with NcoI and NheI compatible ends. The SD21 double-stranded DNA segment was ligated into NcoI/NheI linearized and 5′ dephosphorylated pET24d to create the pET24d-SD21 vector, which contained a new multi-cloning site NcoI-SfiI-NheI-BamHI-EcoRI-SacI-SalI-HindIII-NotI-XhoI with two stop codons directly after the SfiI site for insertion and expression of ELP with the minimum number of extra amino acids.

The pUC19-ELP1 [V₅A₂G₃-60], pUC19-ELP1 [V₅A₂G₃-90], and pUC19-ELP1 [V₅A₂G₃-180] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET15b-SD3 expression vector as described hereinabove to create pET15b-SD3-ELP1 [V₅A₂G₃-60], pET15b-SD5-ELP1 [V₅A₂G₃-90] and pET15b-SD5-ELP1 [V₅A₂G₃-180], respectively.

The pUC19-ELP1 [V₅A₂G₃-90], pUC19-ELP1 [V₅A₂G₃-180], pUC19-ELP1 [V-60] and pUC19-ELP1 [V-120] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET15b-SD5 expression vector as described hereinabove to create pET15b-SD5-ELP1 [V₅A₂G₃-90], pET15b-SD5-ELP1 [V₅A₂G₃-180], pET15b-SD5-ELP1 [V-60] and pET15b-SD5-ELP1 [V-120], respectively.

The pUC19-ELP1 [V₅A₂G₃-90] plasmid produced in XL1-Blue was digested with PflMI and BglI, and the ELP-containing fragment was ligated into the SfiI site of the pET15b-SD6 expression vector as described hereinabove to create pET15b-SD6-ELP1 [V₅A₂G₃-90].

The pUC19-ELP1 [K₁V₂F₁-64], and pUC19-ELP1 [K₁V₂F₁-128] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP1 [K₁V₂F₁-64] and pET24d-SD21-ELP1 [K₁V₂F₁-128], respectively.

The pUC19-ELP1 [K₁V₇F₁-72] and pUC19-ELP1 [K₁V₇F₁-144] plasmids produced in XL1-Blue were digested with PflMI and BglI, and the ELP-containing fragments were ligated into the SfiI site of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP1 [K₁V₇F₁-72], pET24d-SD21-ELP1 [K₁V₇F₁-144], respectively.

The pUC19-ELP2[60] and pUC19-ELP2[120] plasmids produced in XL1-Blue were digested with NcoI and HindIII, and the ELP-containing fragments were ligated into the NcoI and HindIII sites of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP2[60], pET24d-SD21-ELP2[120], respectively.

The pUC19-ELP4[V-60] and pUC19-ELP4[V-120] plasmids produced in XL1-Blue were digested with NcoI and HindIII, and the ELP-containing fragments were ligated into the NcoI and HindIII sites of the pET24d-SD21 expression vector as described hereinabove to create pET24d-SD21-ELP4[V-60], pET24d-SD21-ELP4[V-120], respectively.

Example 2 Isolation and Purification of Fusion Proteins Containing Insulin A Peptide (InsA)

ELP-InsA fusion proteins included the following:

Insulin A peptide and ELP1 [V-60] polypeptide with an enterokinase protease cleavage site therebetween.

Insulin A peptide and ELP1 [V₅A₂G₃-90] polypeptide with an enterokinase protease cleavage site therebetween.

Insulin A peptide and ELP1 [V-120] polypeptide with an enterokinase protease cleavage site therebetween.

Insulin A peptide and ELP1 [V₅A₂G₃-180] polypeptide with an enterokinase protease cleavage site therebetween.

A single colony of E. coli strain BLR (DE3) (Novagen) containing the respective ELP-InsA fusion protein was inoculated into 5 ml CircleGrow (Q-BIOgene, San Diego, Calif.) supplemented with 100 μg/ml ampicillin (Sigma) and grown at 37° C. with shaking at 250 rpm for 5 hours. The 5 ml culture was then inoculated into a 500 ml culture and allowed to grow at 25° C. for 16 hours before inducing with 1 mM IPTG for 4 hours at 25° C. The culture was harvested and suspended in 40 ml 20 mM Tris-HCl pH 7.4, 50 mM NaCl, 1 mM DTT and 1 Complete EDTA free Protease inhibitor pellet (Roche, Indianapolis, Ind.). Cells were lysed by ultrasonic disruption on ice for 3 minutes, which consisted of 10 seconds bursts at 35% power separated by 30 second cooling down intervals. Cell debris was removed by centrifugation at 20,000 g, 4° C. for 30 minutes.

Inverse phase transition was induced by adding NaCl to the cell lysate at room temperature to achieve a final concentration of 1.0 M therein, followed by centrifugation at 20,000 g for 15 minutes at room temperature. The resulting pellet contained the respective ELP-InsA fusion protein and non-specifically NaCl precipitated proteins.

The pellet was re-suspended in 40 ml ice-cold ml 20 mM Tris-HCl pH 7.4, 50 mM NaCl, 1 mM DTT and re-centrifuged at 20,000 g, 4° C. for 15 minutes to remove the non-specifically NaCl precipitated proteins. The inverse transition cycle was repeated two additional times to increase the purity of the respective ELP-InsA fusion protein and reduce the final volume to 0.5 ml.

Example 3 Half-Life of ELP1

The pharmacokinetics of ELP1 were determined by intravenously administering [¹⁴C]ELP1 to nude mice (Balb/c nu/nu) bearing a leg/flank FaDu xenograft and collecting blood samples at various time intervals after administration. The blood pharmacokinetics exhibited a characteristic distribution and elimination response for large macromolecules, which was well described by a bi-exponential process.

The plasma concentration time-course curve was fit to the analytical solution of a two-compartment model to approximate both an elimination and distribution response. Certain pharmakinetic parameters are shown in Table 1 below. The distribution volume of the ELP (1.338 μl) was nearly identical to the hypothetical plasma volume of 1.363 μl (Barbee, R. W., et al., Am. J. Physio. 263(3) (1992) R728-R733), indicating that the ELP did not rapidly distribute or bind to specific organs and tissues directly after administration. The AUC is a measure of the cumulative exposure to ELP in the central compartment or the blood plasma. The body clearance is defined as the rate of ELP elimination in the body relative to its plasma concentration and is the summation of clearance through all organs including the kidney, liver and others.

TABLE 1 Pharmacokinetic parameters calculated for [¹⁴C]ELP1 AUC (mg k₁ (hr⁻¹) k₂ (hr⁻¹) k_(e) (hr⁻¹) V_(d) (μL) ELP hr/ml) Cl_(B) (μL/hr) ELP1-150 3.54 1.99 0.24 1.338 7.1 317

The mass transfer rate constants are from a standard two-compartment model (k₁; from central to peripheral compartment; k₂, from peripheral to central compartment; and k_(e), elimination from central compartment). The distribution volume (V_(d)), central compartment concentration time-course area under the curve (AUC) and body clearance (Cl_(B)) are displayed. Data are shown as the mean values (n=5, except V_(d) and initial plasma concentration (C_(O)) was calculated from a similar cohort with n=3).

Example 4 Biodistribution of ELPS 1N Nude Mice ¹⁴C labeled ELP1-150 and/or ¹⁴C labeled ELP2-160

¹⁴C labeled ELP1-150 and/or ¹⁴C labeled ELP2-160 were administered to nude mice with a FaDu tumor (mean+/−SD, n=6). The tumor was heated post administration of the ELP in a water bath at 41.5° C. The distribution was highest to the organs with the highest blood content: liver, kidneys, spleen, and lungs.

¹⁴C labeled ELP2-N₁A₈G₇-1601

¹⁴C labeled ELP2-[V₁A₈G₇-160] (T_(t)>60° C.) was administered to nude mice for a plasma concentration of 15 μM. ELP concentrations were determined following 1 hour of heating (41° C.) of an implanted FaDu tumor, located in the right hind leg of the nude mouse. Data are shown as the mean, plus the 95% confidence interval. N=6.

ELP concentration was measured 1.5 hours following systemic administration of ¹⁴C labeled ELP2-[V₁A₈G₇-160]. The highest distribution is seen in organs with the highest blood content: liver, kidneys, spleen, and lungs.

Example 5 Exendin-4 ELP Fusion

The DNA sequence for Exendin-4 (Ex-4) (SEQ ID NO: 14) was reverse translated from the amino acid sequence using codons optimized for E. coli expression. The DNA sequence encoding Exendin-4 was constructed by annealing together synthetic oligonucleotides with overhanging 5′ and 3′ ends compatible with the restriction sites NdeI and XhoI in the plasmid pET24d-ELP1-90 (FIG. 1). This plasmid was digested with the restriction enzymes NdeI and XhoI and the annealed DNA sequence was ligated into the cut vector. Insertion was confirmed by restriction digest and DNA sequencing. The resulting plasmid was designated as pET24d-Ex-4 ELP1-90 (FIG. 2A), and the sequence of the resulting Exendin-4-ELP fusion shown in FIG. 2B. Primers for construction of the fusion are also indicated.

pET24d-Ex-4 ELP1-90 was used to transform the E. coli strain BRL (Invitrogen) and selected transformants were grown in media 3 (1.2% Tryptone Peptone, 2.4% yeast extract, 5 g/L casamino acids, 2% glycerol, 2.313 g Potassium phosphate dibasic/L, 12.541 g Potassium phosphate monobasic/L) in shake flasks. Production proceeded by autoinduction by inoculating 10D cells into 1L of media 3 and allowing growth to proceed for 17 hr at 37° C. without addition of inducer. The product was recovered by collection of the cell pellet, sonicated to disrupt the cells and recovered by thermal and/or salt induced transition modulated by the ELP moiety (Improved Non-chromatographic Purification of a Recombinant Protein by Cationic Elastin-like Polypeptides, Dong Woo Lim, Kimberly Trabbic-Carlson, J. Andrew MacKay, and Ashutosh Chilkoti. Biomacromolecules 2007, 8, 1417-1424).

This example is with the ELP designated 1-90. This is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10 unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat where X is a V, G, A and Win the ratio 4:3:2:1.

[(VPGXG)10]₉ where the X residue in the ten sequential iterations of the repeat unit (numerical subscript) can be described as [(V_(1, 4, 5, 6, 10)G_(2, 7, 9)A_(3, 8))₈ (V_(1, 4, 5, 6)G_(2, 7, 9)A_(3, 8) W₁₀)].

The ELP may be any combination of VPGXG (SEQ ID NO: 3) units where X is any of the 20 natural amino, acids, except proline, in any combination of repeat units of any length. In addition, the amino acid may be an unnatural amino acid for which the host strain has been engineered to accept an engineered tRNA for incorporation at specific codon (Wang L, Brock A, Herberich B, Schultz P G. Expanding the genetic code of Escherichia coli. [2001] Science 292, 498-500).

This construct was produced in the cytosol with an N-terminal methionine, which is normally removed by methionine aminopeptidase. Complete and accurate processing of the methionine, however, cannot be assumed; this enzyme may also remove the N-terminal histidine of the Exendin-4 moiety. This could result in a mixture of, unprocessed, processed and incorrectly processed products. Consequently, further constructs were developed to generate products with correctly processed N-termini.

Primers were designed to add a Tev protease (Tobacco Etch Virus cysteine protease) cleavage site between the N-terminal methionine and the histidine at the N-terminus of Exendin-4. This allows for removal of the methionine and the Tev recognition sequence to give the mature N-terminus of Exendin-4 (histidine). This can be done post-production or the Tev protease can be co-expressed to cleave the recognition sequence during production, for instance, as an intein (Ge, X., Yang, D. S. C., Trabbic-Carlson, K., Kim, B., Chilkoti, A. and Filipe, C. D. M. Self-Cleavable Stimulus Responsive Tags for Protein Purification without Chromatography. J. Am. Chem. Soc. 127, 11228-11229, 2005). The Tev Exendin-4 sequence is shown in FIG. 3A. FIG. 3B shows additional sequences added, labeled as “Linker Tev,” provide a better target for the Tev protease.

An alternative route to obtaining a correctly processed N-terminus for Ex-4 is to use a leader or signal sequence that directs the product to the periplasm and which is cleaved by a signal peptidase in the process. In this instance, a signal sequence, DsbA, that directs the transcript to the signal recognition particle for direct secretion of the polypeptide into the periplasm is given. (See FIG. 4A). The plasmid pET24d-DsbA-Ex-4 ELP1-90 is shown in FIG. 4B.

While this example illustrates the preparation of therapeutic agents with Exendin-4 sequences, such sequences can be replaced with GLP-1, insulin, Factor VII/VIIa, or other therapeutic protein listed in Table 1, generated in exactly or a similar manner as detailed for Exendin-4.

Example 6 GLP1-ELP Fusion Protein

The ELP plasmid constructs were used to prepare two GLP1-ELP fusion proteins, GLP1(A8G,7-37) ELP1-90 and GLP1(A8G,7-37) ELP1-120. The plasmid contructs, fusion-encoding nucleotide sequence, as well as the amino acid sequence of the resulting fusion proteins are shown in FIGS. 5 and 6.

Both constructs contain an N-terminal Tev protease site to allow processing to the mature form where His⁷ of GLP1 is at the N-terminus. The processed fusion proteins have calculated molecular weights of about 39,536 and about 50,828, respectively.

Example 7 FVII ELP Fusion Protein

The coagulation factor VII (FVII) gene was modified by PCR from a cDNA clone (Oragene) to add restriction sites at the 5′ and 3′ ends for cloning into the ELP-containing vector. At the 5′ end an NheI site was added and at the 3′ end a NotI site was added. The DNA and amino acid sequences of the Factor VII gene are shown in the accompanying Sequence Listing as SEQ ID NOS: 34 and 33, respectively. The DNA sequences of the 5′ and 3′ primers used to PCR amplify the factor VII (FVII) gene were:

(SEQ ID NO.: 49) P13: CTAGCTAGCATGGTCTCCCAGGCCCTC (SEQ ID NO.: 50) P14: TATTCTTGCGGCCGCGGGAAATGGGGCTCGCAG

The resulting PCR fragment was digested with the restriction enzymes NheI and NotI and ligated into the plasmid pcDNA3.1+ELP1-90 previously digested with the restriction enzymes NheI and NotI (FIG. 7A).

The resulting plasmid, pcDNA3.1+FVII-ELP1-90, was transiently transfected into HEK293 cells and culture media harvested. The ELP fusion was purified by phase transition (FIGS. 9 and 10).

The nucleotide and amino acid sequences of the FactorVII-ELP fusion is shown in FIG. 7B. As shown, the FactorVII-ELP fusion protein contains a Tev protease linker between the FactorVII component and the ELP component. This linker is optional.

Example 8 Insulin ELP Fusion Protein

The cDNA for the human insulin gene is modified at the 5′ and 3′ ends for insertion in to pET24d-ELP1-90. The 5′ primer adds an N-terminal methionine for bacterial expression and an NdeI restriction enzyme site. The 3′ primer adds an XhoI restriction enzyme site. The PCR product and the plasmid are both digested with the restriction enzymes NdeI and XhoI and ligated together. The sequence of the insulin (Chains B, C, and A fused to ELP1 is shown in FIG. 8A.

Correct insertion is determined by restriction digest and DNA sequencing. The resulting plasmid, designated pET24d Insulin-ELP1-90, is shown in FIG. 8B.

The native insulin form is generated after recovery from E. coli by treatment with trypsin and carboxypeptidase B to remove the C-peptide chain.

For correct processing of the N-terminus of the B-chain similar modifications to those made for the Exendin-4 fusion (protease cleavage site, signal sequence) can be implemented (see Example 4). Alternatively, the first two residues can be Met-Arg, which can also be removed by trypsin digestion in production of the final material (R. M. Belagaje, S. G. Reams, S. C. Ly and W. F. Prouty, Increased production of low molecular weight recombinant proteins in Escherichia coli. Protein Sci. 6, 1953-1962, 1997).

Additional constructs would place the insulin cDNA at the 3′ end of the ELP for a C-terminal fusion, add linkers between the Insulin and ELP sequences, and/or use modified forms of insulin which have no C-peptide (single chain insulins as described) removing the need for additional processing.

Example 9 Synthesis of the ELP Gene for Conjugation

A gene encoding a 50 amino acid sequence was constructed from chemically-synthesized oligonucleotides using standard molecular biology protocols. The 50 amino acid sequence contained 10 repeats of the pentapeptide VPGXG (SEQ ID NO: 3), where the guest residues (V, G, and A in a 5:3:2 molar ratio) were selected to provide a Tt of 40° C. The gene was oligomerized end-to-end by standard molecular biology techniques, to produce an oligomeric ELP gene. Additionally a single 50 amino acid sequence was constructed containing the 10 repeat pentapeptide VPGXG (SEQ ID NO: 3) polypeptide where the guest residues were V, G, A and C in a 4:3:2:1 molar ratio. This sequence could be added at any cycle of the oligomerization process to introduce a single cysteine residue into the final construct at a chosen point along the length of the construct.

The example given here is with the ELP designated 1-90. This is based on the VPGXG (SEQ ID NO: 3) motif where X is a V, G or A in the ratio 5:3:2 in a 10-unit repeat, repeated 8× with a final (C-terminal) 10-unit repeat where X is a V, G, A and C in the ratio 4:3:2:1, i.e., [(VPGXG)10]9 (SEQ ID NO.: 3).

Alternatively, the residue could be one of either arginine, lysine, aspartic acid or glutamic acid. The purpose of these amino acids is to provide a reactive side chain for the chemical conjugation of, for example, insulin. In this particular case the use of an ELP would be to extend the circulating half-life of the therapeutic protein (e.g., insulin) to provide prolonged basal glucose control. Conjugated to an ELP that transitions at body temperature, the insulin would form a precipitated depot at the site of injection in a similar manner to Lantus® (Sanofi Aventis) but without the requirement for formulation in acidic (pH 4.0) conditions with m-cresol for a more tolerable injection.

Example 10 Potency and Half-Life of Factor VII-ELP

FIG. 11 shows the activation of Factor X by FactorVIIa-ELP1-90, and by Factor VIIa as a comparison. Factor VII-ELP was produced in HEK cells. Factor VIIa was derived from human plasma. As shown, FactorVIIa-ELP retains full activity.

When administered to rats by i.v., Factor VII-ELP demonstrated a half-life of about 690 minutes. In contrast, Factor VII demonstrated a half-life of 45-60 minutes. Half-life in this example was measured by sandwich ELISA for FactorVII. FIG. 12.

Also in contrast, the reported half-life for NovoSeven™ is 45 minutes, the reported half-life for FactorVIIa-albumin fusion is 263 minutes, and the reported half-life for Factor VIIa-PEG is 300 minutes in mice and 600 minutes in dog.

Example 11 GLP-1 (or Exendin-4) In Vitro Bioassay

Activation of the GLP-1 receptor (GLP1R) results in production of cAMP secondary messenger within the cell. Therefore, GLP-1 or Exendin-4 analogs and corresponding therapeutic agents may be tested by their ability to activate GLP1R on the cell surface and produce cAMP.

For this bioassay CHO cells transfected with cDNA coding for GLP1R are used. These cells respond to stimulation by GLP-1 and produce high levels of cAMP. Log phase growing cells are plated and increasing concentrations of test compounds (e.g., therapeutic agent of the invention, or GLP-1 or exendin-4 functional analog) are added to the cells. After an appropriate incubation period (usually 15-60 min) in physiological buffer at 37° C. the cAMP produced is measured using a CatchPoint cAMP assay kit from Molecular Devices (Sunnyvale, Calif.). The EC₅₀ of each test compound as compared to GLP-1 peptide or Exendin-4 peptide (or as compared to an unfused or unconjugated counterpart of a therapeutic agent of the invention) is indicative of the changes in activity due to a specific modifications introduced into the peptide, or due to particular chemical or recombinant coupling to an ELP component.

As shown in FIG. 13, both GLP1-ELP (PB0868) and Exendin-4-ELP (PB 0859) maintain high activity in vitro, shown in comparison to Exendin alone. It is of note that the specific activity of Albugon® and Liraglutide® run 50-100 fold less than the exendin peptide.

Example 12 GLP-1 (or Exendin-4) In Vivo Bioassay

The activity of GLP-1 or Exendin analogues or corresponding therapeutic agents may be tested in animals. For this assay, normal or diabetic animals may be used. Diabetic animals with blood glucose concentration 300-500 mg/dl are injected with different doses of GLP-1 or Exendin analogues or corresponding therapeutic agent, and changes in blood glucose monitored with a glucometer. The drop in glucose at different times points post administration is compared to that resulting with standard amounts of GLP-1 or Exendin-4 peptide, or compared to an unfused or unconjugated counterpart of a therapeutic agent of the invention. Alternatively, the blood glucose excursion in normal or diabetic animals during specific time period after administration of exogenous glucose is compared to GLP-1 or Exendin-4 (or to unfused or unconjugated counterparts of therapeutic agents). In this way the activity of the analogues and fusion proteins can be compared to the natural peptides.

FIG. 14 shows the pharmacokinetics of GLP1-ELP1-120 in rats administered both by i.v. and subcutaneously. Three rats were used for each time point. The dose was ˜10 mg/kg. The T₁₁₂ when administered by i.v. was about 12.9 hours. The T_(1/2) when administered subcutaneously was about 8.6 hours.

FIG. 15 shows the pharmacokinetics of GLP1-ELP1-120 in rabbits administered both by i.v. and subcutaneously. Three rabbits were used for each time point. The dose was ˜1 mg/kg. The T_(1/2) when administered by i.v. was about 20 hours. The T_(1/2) when administered subcutaneously was about 24 hours.

FIG. 16 shows the sustained glycemic control in diabetic mice with GLP1-ELP1-90.

All reference cited herein are hereby incorporated by reference in their entireties. While the invention has been has been described herein in reference to specific aspects, features and illustrative embodiments of the invention, it will be appreciated that the utility of the invention is not thus limited, but rather extends to and encompasses numerous other variations, modifications and alternative embodiments, as will suggest themselves to those of ordinary skill in the field of the present invention, based on the disclosure herein. 

What is claimed is:
 1. A therapeutic agent comprising a recombinant fusion between an elastic polypeptide and a therapeutic peptide, the therapeutic agent being formulated with a pharmaceutically acceptable carrier or excipient suitable for parenteral administration, and the therapeutic agent having an extended circulatory half-life when compared to the therapeutic peptide alone, wherein: the therapeutic peptide comprises a GLP-1 receptor agonist, and is at the N-terminus of the therapeutic agent; and the elastic polypeptide is not less than 50 kpa and has a pattern of proline-containing beta-turns forming an extended, non-globular structure, with no tertiary structure.
 2. The therapeutic agent of claim 1, wherein the elastic polypeptide forms a spiral conformation.
 3. The therapeutic agent of claim 1, wherein the elastic polypeptide comprises repeat amino acid motifs.
 4. The therapeutic agent of claim 1, wherein the therapeutic agent is formulated for injection.
 5. The therapeutic agent of claim 4 wherein the therapeutic agent is formulated for subcutaneous injection.
 6. The therapeutic agent of claim 5, wherein the therapeutic agent is formulated for injection from about once to about five times per month.
 7. The therapeutic agent of claim 4, wherein the therapeutic agent is formulated for intramuscular injection.
 8. The therapeutic agent of claim 7 wherein the therapeutic agent is formulated for injection from about once to about five times per month.
 9. The therapeutic agent of claim 1, wherein the GLP-1 receptor agonist is GLP-1 (7-37), GLP-1 (7-36), or exendin, each optionally having from 1 to 3 amino acid modifications independently selected from an insertion, deletion, and/or substitution.
 10. A therapeutic agent comprising a recombinant fusion between an elastic polypeptide and a therapeutic peptide, the therapeutic agent being formulated with a pharmaceutically acceptable carrier or excipient suitable for parenteral administration, and the therapeutic agent having an extended circulatory half-life when compared to the therapeutic peptide alone, wherein: the therapeutic peptide comprises a GLP-1 receptor agonist, and is at the N-terminus of the elastic polypeptide; the elastic polypeptide has a pattern of proline-containing beta-turns forming an extended, non-globular structure, with no tertiary structure, the elastic polypeptide consisting essentially of glycine and hydrophobic amino acids selected from alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, and methionine, and optionally serine, threonine, and glutamic acid, and the elastic polypeptide has a molecular weight of not less than 50 kpa.
 11. The therapeutic agent of claim 10, wherein the elastic polypeptide forms a spiral conformation.
 12. The therapeutic agent of claim 10, wherein the elastic polypeptide comprises repeat amino acid motifs.
 13. The therapeutic agent of claim 10, wherein the therapeutic agent is formulated for injection.
 14. The therapeutic agent of claim 13, wherein the therapeutic agent is formulated for subcutaneous injection.
 15. The therapeutic agent of claim 14, wherein the therapeutic agent is formulated for injection from about once to about five times per month.
 16. The therapeutic agent of claim 14, wherein the therapeutic agent is formulated for intramuscular injection.
 17. The therapeutic agent of claim 16, wherein the therapeutic agent is formulated for injection from about once to about five times per month.
 18. The therapeutic agent of claim 10, wherein the GLP-1 receptor agonist is GLP-1 (7-37), GLP-1 (7-36), or exendin, each optionally having from 1 to 3 amino acid modifications independently selected from an insertion, deletion, and/or substitution.
 19. The therapeutic agent of claim 10, wherein the elastic polypeptide contains amino acids selected from alanine, serine, threonine, and glutamic acid. 